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News Article | May 8, 2017
Site: www.prnewswire.com

The initial study will assess immune responses of 10 healthy adults (ages 40-80) to a licensed hepatitis B vaccine. It will feature one of the most comprehensive analyses of how people respond to vaccinations to learn why some individuals are protected from a single dose, while others are not. The study will expand to include several hundred people – from neonates to the elderly in middle and low-income countries. "Developing a better understanding of why some groups of people are protected from disease is a goal that simply must be achieved," said Co-Principal Investigator Tobias Kollmann, M.D., Ph.D., professor of pediatrics at the University of British Columbia (UBC) and an investigator at the Vaccine Evaluation Center in Vancouver, Canada. "The licensed hepatitis B vaccine, which only works in about 30 percent of people on the first shot, is an ideal model vaccine to study general principles of human immunological protection because it is one of the few vaccines for which we know how it protects." The study will take place at the at the Vaccine Evaluation Center, in Vancouver, Canada, and will be augmented by extensive immunological and bioinformatic analyses at the Project's San Diego Mesa Consortium, which includes the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, and UC San Diego, with clinical coordination by the Vanderbilt Institute for Clinical and Translational Research. "With technological advances in biomedical, computational and engineering sciences, we have an unprecedented opportunity to decipher the immune system's components and core principles required to generate long-lasting immunity against disease, and usher in a new era of global health," added Stanley Plotkin, M.D., Chairman of the Human Vaccines Project's Board of Directors. About the Human Vaccines Project| The Human Vaccines Project is a nonprofit public-private partnership with a mission to decode the human immune system to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies. Support and funding for the Project includes the Robert Wood Johnson Foundation, John D. and Catherine T. MacArthur Foundation, GSK, Illumina, MedImmune, Sanofi Pasteur, Crucell/Janssen, Regeneron, Pfizer, Moderna, Boehringer Ingelheim, Aeras, Vanderbilt University Medical Center, UC San Diego, The Scripps Research Institute, J. Craig Venter Institute and La Jolla Institute for Allergy and Immunology. To learn more, visit www.humanvaccinesproject.org. For media inquiries, please contact Kierstin Coatney, Kierstin@globalgatewayadvisors.com or +1-716-378-1602. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/new-study-aims-to-explain-the-rules-of-how-the-immune-system-works-300453028.html


News Article | November 17, 2016
Site: www.prweb.com

The Human Vaccines Project and Boehringer Ingelheim are pleased to announce a three-year collaboration agreement to support their mutual objective to decode the human immune system with the aim of accelerating understanding and development of immunotherapies overall as well as better vaccines for cancer treatment. Under the terms of the agreement, Boehringer Ingelheim’s contributions to the Project will help catalyze the Project’s expanding programs. “We are tremendously honored that Boehringer Ingelheim has elected to partner with the Project, joining a growing number of leading, global biopharmaceutical companies committed to addressing the key scientific challenges impeding development of next generation vaccines and immunotherapies,” said Wayne C. Koff, Ph.D., President and CEO of the Human Vaccines Project. “Boehringer Ingelheim brings exceptional basic science and clinical research expertise in the areas of oncology and human immunology, and is at the forefront of biopharma innovation in these areas.” A revolution is ongoing in cancer immunotherapy, due to the recent realization of the importance of “checkpoints,” proteins that enable tumors to evade the immune system’s ability to kill the tumor, and novel therapeutics termed “checkpoint inhibitors” that have provided dramatic clinical benefit in managing a subset of cancers in a limited number of patients. “Despite these exciting breakthroughs, our understanding of how the immune system can best be harnessed to attack and eliminate tumors remains limited. A better understanding of the human immune system in healthy individuals as well as patients, and how best to measure and direct the immune system is needed,” said Clive R. Wood, Ph.D., Senior Corporate Vice President, Discovery Research at Boehringer Ingelheim. “We are pleased to become a partner in this groundbreaking project which offers the potential to open a new era in vaccine and immunotherapeutic development. This complements our strong commitment to cancer immunology with a pipeline that includes among others, a therapeutic cancer vaccine and next generation checkpoint inhibitors.” Within the Human Vaccines Project’s scientific network, investigators at leading academic research centers are seeking to determine the central components of the human immune system at the molecular and structural level, as well as the common rules by which the immune system generates specific and durable protective responses against a range of infectious and neoplastic diseases. Successful achievement of these goals should enable accelerated development of new and improved vaccines and therapeutics for major global diseases. “The Human Vaccines Project is one of the more promising projects to help transform the future of vaccine development and cancer immunotherapy. JCVI is pleased to be adding our bioinformatics acumen as part of this effort to help conquer some of the most devastating diseases of the 21st century,” said J. Craig Venter, Founder, Chairman and CEO of the J. Craig Venter Institute which recently joined together with the Scripps Research Institute, La Jolla Institute and UC San Diego to serve as a scientific hub for the Project. About the Human Vaccines Project The Human Vaccines Project is a non-profit public-private partnership with the mission to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers by decoding the human immune system. The Project has a growing list of partners and financial supporters including: Vanderbilt University Medical Center, the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, UC San Diego, Aeras, Crucell/Janssen, GSK, Pfizer, MedImmune, Regeneron, Sanofi Pasteur, the Robert Wood Johnson Foundation and the John D. and Catherine T. MacArthur Foundation. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies, and has been endorsed by 35 of the world’s leading vaccine scientists.


News Article | December 12, 2016
Site: www.eurekalert.org

Members of the TET family of proteins help protect against cancer by regulating the chemical state of DNA --and thus turning growth-promoting genes on or off. The latest findings reported by researchers at La Jolla Institute for Allergy and Immunology illustrate just how important TET proteins are in controlling cell proliferation and cell fate. For the study, published in the December 20, 2016, edition of Nature Immunology, Anjana Rao, PhD, a professor at the La Jolla Institute, genetically engineered mice to lack both TET2 and TET3 in T cells. The mice developed a lethal disease resembling lymphoma within weeks of birth, their spleens and livers bloated with iNKT cells, a normally rare kind of T cell. This finding recapitulated the features of many human blood cancers, including those involving T cells, in which TET2 is often mutated or lost. "We knew that TET proteins were involved in human cancer but we didn't know how they regulated T cell development," says Angeliki Tsagaratou, Ph.D., an instructor in the Rao lab and the study's first author. "In the new study we saw huge increases in the proliferation of the special iNKT cells in TET2/3 mutant mice. Once growth control was lost, those cells underwent the kind of malignant transformation that gives rise to T cell lymphoma in humans." The results demonstrate how TET proteins serve as anti-cancer factors called tumor suppressors and suggest ways to block malignancy in cancers marked by TET mutations. Members of the TET family of enzymes help rewrite the epigenome, the regulatory layer of chemical modifications that sits atop the genome and helps determine gene activity without changing the letters of DNA. In addition to the four letters or bases in DNA - A, C, G and T - there is a "fifth base" with a very important role. This base is formed from the DNA base cytosine (C) by addition of a methyl group, and so is called mC (m for methyl). The levels of mC are altered in cancer cells and during the development of embryos. However, until the discovery of TET proteins in 2009 in the laboratory of Rao, then at Harvard Medical School, it was not known how mC could be converted back to regain C. Dr. Rao's team showed that TET proteins were able to convert 5mC to a sixth base, known as 5hmC. 5hmC is indirectly converted back to C, thus restoring the status quo. DNA modifications of this type in part govern how compressed and "expressible" a strand is: in general, DNA methylation coils up genes to silence them, while less methylated DNA strands, or strands that possess 5hmC, are more accessible and more likely to be expressed, which means they are directing the synthesis of a particular protein. "When TET proteins are lost, iNKT cells that lack them apparently become trapped in an immature, highly proliferative state," explains Tsagaratou. "Unlike normal cells, they can't switch off growth-promoting genes: they just keep dividing." DNA sequencing followed by bioinformatic data-crunching revealed the kinds of abnormal DNA methylation patterns typically seen after TET protein loss. That suggested that improper DNA modifications in the TET2/3 mutant T cells allowed unchecked expression of cancer- and inflammation-associated genes. Edahí González-Avalos, one of the two second authors of the study, conducted most of that analysis. "Without computer analysis of sequencing results, we would not have been able to determine relationships between DNA methylation, how accessible regions of the genome were, global gene expression, or the emergence of cancer cells," says González-Avalos, a graduate student in UCSD's Bioinformatics Graduate Program. "Without computational tools, this study could have taken many, many years!" A critical test reported in the paper demonstrates how insidious even a few perpetually immature iNKT cells can be. In it, the team transferred a small number of iNKT cells lacking Tet2/3 from mutant mice into adult mice with a robust immune system. But even those mice soon developed lymphoproliferative disease as lethal as that seen in TET2/3 mutant mice. "We weren't expecting this," says Tsagaratou. "When we transferred mutant cells we thought healthy mice would control their expansion. But in three months mutant cells took over the mouse's immune system and rapidly gave rise to tumors." The lesson of this story? That a functional immune system is no defense against malignancy once deregulated, pro-inflammatory iNKT cells gain a foothold. In a 2015 Nature Communications paper, Rao, who heads LJI's Division of Signaling and Gene Expression, reported that TET2/3 mutations caused myeloid disease resembling acute myeloid leukemia in mice. The new study extends these findings to a different class of hematological cancers, namely lymphoid cancer, which is caused by abnormal activity of immune T or B cells. "Right now we don't know how TET mutations specifically contribute to either T cell lymphomas or leukemias. But we think these mutations are early events in both," says Tsagaratou. Thus the search is on is to discover additional cancer-causing genes "downstream" of TET mutations that drive uncontrolled cell division in either context. "Identification of additional factors would give us a broad idea of all steps in pathway and provide multiple targets to hit." In addition to Tsagaratou and González-Avalos, Sini Rautio of Aalto University School of Science, in Aalto, Finland, was a co-second author of the paper, contributing significantly to the bioinformatic analysis of genome-wide sequencing data. Also contributing were James Scott Browne, Ph.D., Susan Togher, and William A. Pastor, Ph.D., all from LJI; Ellen V. Rothenberg, Ph.D., of Caltech; and bioinformaticians Lukas Chavez Ph.D., of the German Cancer Research Center in Heidelberg and Harri Lähdesmäki, Ph.D., of Aalto University School of Science, the PhD thesis supervisor of Sini Rautio. The study was funded by the NIH (R01 grants AI44432, CA151535 and R35CA210043); a Leukemia & Lymphoma Society grant (6187-12, to A.R.); and an Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research grant (to H.L.). Other funding was from the Cancer Research Institute, the Academy of Finland Centre of Excellence in Molecular Systems, Immunology and Physiology Research program, the Damon Runyon Cancer Research Foundation (DRG-2069-11), and the National Science Foundation. doi:10.1038/ni.3630 About La Jolla Institute for Allergy and Immunology The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.


Drescher K.M.,Creighton University | von Herrath M.,NovoNordisk and nter | von Herrath M.,La Jolla institute | Tracy S.,University of Nebraska Medical Center
Reviews in Medical Virology | Year: 2015

Summary: Enteroviruses and humans have long co-existed. Although recognized in ancient times, poliomyelitis and type 1 diabetes (T1D) were exceptionally rare and not epidemic, due in large part to poor sanitation and personal hygiene which resulted in repeated exposure to fecal-oral transmitted viruses and other infectious agents and viruses and the generation of a broad protective immunity. As a function of a growing acceptance of the benefits of hygienic practices and microbiologically clean(er) water supplies, the likelihood of exposure to diverse infectious agents and viruses declined. The effort to vaccinate against poliomyelitis demonstrated that enteroviral diseases are preventable by vaccination and led to understanding how to successfully attenuate enteroviruses. Type 1 diabetes onset has been convincingly linked to infection by numerous enteroviruses including the group B coxsackieviruses (CVB), while studies of CVB infections in NOD mice have demonstrated not only a clear link between disease onset but an ability to reduce the incidence of T1D as well: CVB infections can suppress naturally occurring autoimmune T1D. We propose here that if we can harness and develop the capacity to use attenuated enteroviral strains to induce regulatory T cell populations in the host through vaccination, then a vaccine could be considered that should function to protect against both autoimmune as well as virus-triggered T1D. Such a vaccine would not only specifically protect from certain enterovirus types but more importantly, also reset the organism's regulatory rheostat making the further development of pathogenic autoimmunity less likely. © 2014 John Wiley & Sons, Ltd.


News Article | November 12, 2016
Site: www.PR.com

Receive press releases from San Diego Advisor of the Year: By Email Advisor of the Year Recognizes 2016 Award Winners at Second Annual Event Leading business professionals in San Diego honored for stellar leadership and outstanding accomplishments in the M&A community San Diego, CA, November 12, 2016 --( Feted were the following: · Andrew Ruff, TGC Accounting (Sell-side preparation by a CPA firm), · Bruce Strumlauf, LevitZacks (Financial and tax strategy for a deal over $25 million), · Channing Hamlet, Objective Capital Partners (Sell-side investment banking over $25 million) · Cheston Larson, Latham & Watkins (Sell-side legal representation to a public company – Deal size over $25 million) · David Noosinow, BNY Mellon (Long-term exit planning) · Hayden Trubitt, Stradling, Yocca Carlson & Rauth (Sell-side legal representation to a private company – Deal size over $25 million) · John D. Tishler, SheppardMullin (Advice for an internal transition – Deal size under $25 million) · Michael Brown, Stradling Yocca Carlson & Rauth (Sell-side legal representation to a private company – Deal size under $25 million) · Mike Friedman, LevitZacks (Financial and tax strategy for a deal under $25 million) · Michel Kim, Objective Capital Partners (Internal transition advice), · Nancy G. Henderson, Henderson Caverly Pum & Charney (Pre-transaction planning), · Patrick Monroe, Best Best & Krieger (Buy-side legal representation – Deal under $25 million) · Paul Johnson, Procopio (Sell-side legal representation in sale to a public company – Deal size under $25 million) · Steve LaSala, SheppardMullin (Buy-side legal representation – Deal size over $25 million) · Todd Wilson & Joel Weinstein, W Partners (Buy-side investment banking & growth capital design and execution) · Trever Acers, Objective Capital Partners (Advice for internal transition – Deal size under $25 million) · Wade Hansen, Cabrillo Advisors (Sell-side investment banking – Deal size under $25 million). “Advisor of the Year is especially proud to announce the winners of this year’s awards,” says Paul Thiel, managing director of BNY Mellon’s San Diego practice. “This recognition shines a light on the deserving people behind the impressive deals in San Diego’s M&A community.” The judging panel was led by former Broadcom chairman John Major and Histogen founder and CEO Gail Naughton, and included representatives from UCSD’s Rady School of Management, CSU San Marcos’ School of Business and the La Jolla Institute, as well as several entrepreneurs who have successfully navigated the M&A process. In addition to the recognition, select winners will be invited to participate as featured speakers at subsequent events, including the Association for Corporate Growth conference, “The Deals Behind the Advisor of the Year,” to be held at Lomas Santa Fe Country Club on Tuesday, November 15. A major highlight of the 2016 Advisor of the Year event was the lively “GameChangers: Women in the C-Suite” session. Moderated by Emily Rex, CEO of Departure, the panel featured San Diego’s police chief Shelley Zimmerman, the San Diego Chargers’ Jeanne Bonk, Port Brewing Company’s Gina Marsaglia and leadership consultant Cindy Candela sharing their personal experiences working - and succeeding - in traditionally male-dominated industries. Local legendary entrepreneur Ernest Rady delivered an impactful keynote address. Net proceeds from the event will benefit the Institute. “We’d like to thank everyone who attended and took part in making this year’s Advisor of the Year event a big success,” says Thiel. “We also are grateful to our sponsors and look forward to continuing to bring attention to the great work that is happening daily in San Diego’s business community.” Sponsors of the 2016 Advisor of the Year program are: BDO; Best Best & Krieger; Cabrillo Advisors; CBIZ; Claiborne Advisors; Deloitte; Departure; Friedman Brannen; Haskell & White; Henberger Group; HetzelMeade Communications; LevitZacks CPA, Lindsay & Brownell; NFP Insurance Brokerage & Consulting; Objective Capital Partners; Our City magazine; Polito Eppich; Procopio; RA Capital Advisors; Stradling; SheppardMullin; Torrey Pines Bank; Vantage Point Advisors and W Partners. About Advisor of the Year Advisor of the Year is a not-for-profit unincorporated community association that hosts an annual awards event to recognize and celebrate local advisors who provide extraordinary service and value to owners of middle market companies in the sale, expansion or recapitalization of their companies. The organization also conducts educational workshops and commissions primary research on business and financial trends that affect advisors and their clients. Select winners will be featured in the November ACG program, “The Deals Behind the Advisor of the Year awards.” About La Jolla Institute La Jolla Institute for Allergy and Immunology is located at 9420 Athena Circle in La Jolla and is dedicated to understanding the intricacies and power of the immune system to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®. San Diego, CA, November 12, 2016 --( PR.com )-- The San Diego Advisor of the Year organization today announced the winners of its annual awards recognizing individuals who displayed extraordinary service in supporting the sale, acquisition or recapitalization of a company on behalf of their clients. The recipients were named during the annual awards program and ceremony, hosted by title sponsor BNY Mellon Wealth Management and held at the world-renowned La Jolla Institute for Allergy and Immunology on October 27.Feted were the following:· Andrew Ruff, TGC Accounting (Sell-side preparation by a CPA firm),· Bruce Strumlauf, LevitZacks (Financial and tax strategy for a deal over $25 million),· Channing Hamlet, Objective Capital Partners (Sell-side investment banking over $25 million)· Cheston Larson, Latham & Watkins (Sell-side legal representation to a public company – Deal size over $25 million)· David Noosinow, BNY Mellon (Long-term exit planning)· Hayden Trubitt, Stradling, Yocca Carlson & Rauth (Sell-side legal representation to a private company – Deal size over $25 million)· John D. Tishler, SheppardMullin (Advice for an internal transition – Deal size under $25 million)· Michael Brown, Stradling Yocca Carlson & Rauth (Sell-side legal representation to a private company – Deal size under $25 million)· Mike Friedman, LevitZacks (Financial and tax strategy for a deal under $25 million)· Michel Kim, Objective Capital Partners (Internal transition advice),· Nancy G. Henderson, Henderson Caverly Pum & Charney (Pre-transaction planning),· Patrick Monroe, Best Best & Krieger (Buy-side legal representation – Deal under $25 million)· Paul Johnson, Procopio (Sell-side legal representation in sale to a public company – Deal size under $25 million)· Steve LaSala, SheppardMullin (Buy-side legal representation – Deal size over $25 million)· Todd Wilson & Joel Weinstein, W Partners (Buy-side investment banking & growth capital design and execution)· Trever Acers, Objective Capital Partners (Advice for internal transition – Deal size under $25 million)· Wade Hansen, Cabrillo Advisors (Sell-side investment banking – Deal size under $25 million).“Advisor of the Year is especially proud to announce the winners of this year’s awards,” says Paul Thiel, managing director of BNY Mellon’s San Diego practice. “This recognition shines a light on the deserving people behind the impressive deals in San Diego’s M&A community.”The judging panel was led by former Broadcom chairman John Major and Histogen founder and CEO Gail Naughton, and included representatives from UCSD’s Rady School of Management, CSU San Marcos’ School of Business and the La Jolla Institute, as well as several entrepreneurs who have successfully navigated the M&A process.In addition to the recognition, select winners will be invited to participate as featured speakers at subsequent events, including the Association for Corporate Growth conference, “The Deals Behind the Advisor of the Year,” to be held at Lomas Santa Fe Country Club on Tuesday, November 15.A major highlight of the 2016 Advisor of the Year event was the lively “GameChangers: Women in the C-Suite” session. Moderated by Emily Rex, CEO of Departure, the panel featured San Diego’s police chief Shelley Zimmerman, the San Diego Chargers’ Jeanne Bonk, Port Brewing Company’s Gina Marsaglia and leadership consultant Cindy Candela sharing their personal experiences working - and succeeding - in traditionally male-dominated industries. Local legendary entrepreneur Ernest Rady delivered an impactful keynote address. Net proceeds from the event will benefit the Institute.“We’d like to thank everyone who attended and took part in making this year’s Advisor of the Year event a big success,” says Thiel. “We also are grateful to our sponsors and look forward to continuing to bring attention to the great work that is happening daily in San Diego’s business community.”Sponsors of the 2016 Advisor of the Year program are: BDO; Best Best & Krieger; Cabrillo Advisors; CBIZ; Claiborne Advisors; Deloitte; Departure; Friedman Brannen; Haskell & White; Henberger Group; HetzelMeade Communications; LevitZacks CPA, Lindsay & Brownell; NFP Insurance Brokerage & Consulting; Objective Capital Partners; Our City magazine; Polito Eppich; Procopio; RA Capital Advisors; Stradling; SheppardMullin; Torrey Pines Bank; Vantage Point Advisors and W Partners.About Advisor of the YearAdvisor of the Year is a not-for-profit unincorporated community association that hosts an annual awards event to recognize and celebrate local advisors who provide extraordinary service and value to owners of middle market companies in the sale, expansion or recapitalization of their companies. The organization also conducts educational workshops and commissions primary research on business and financial trends that affect advisors and their clients. Select winners will be featured in the November ACG program, “The Deals Behind the Advisor of the Year awards.”About La Jolla InstituteLa Jolla Institute for Allergy and Immunology is located at 9420 Athena Circle in La Jolla and is dedicated to understanding the intricacies and power of the immune system to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®. Click here to view the list of recent Press Releases from San Diego Advisor of the Year


News Article | November 1, 2016
Site: www.eurekalert.org

LA JOLLA, CA--The cornerstone of genetics is the loss-of-function experiment. In short, this means that to figure out what exactly gene X is doing in a tissue of interest--be it developing brain cells or a pancreatic tumor--you somehow cut out, switch off or otherwise destroy gene X in that tissue and then watch what happens. That genetic litmus test has been applied since before people even knew the chemical DNA is what makes up genes. What has changed radically are the tools used by biologists to inactivate a gene. Until now, scientists wishing to delete a gene in a model organism like a mouse did it by clipping out stretches of DNA encoding entire genes or very big chunks of them from the animal's genome. This type of gene "knockout" is what La Jolla Institute for Allergy and Immunology (LJI) investigator Catherine C. Hedrick, Ph.D., used in 2011, when her lab discovered that mice without the gene Nr4a1 lack an anti-inflammatory subtype of white blood cells, nicknamed 'patrolling monocytes'. Now, the Hedrick group's latest study reports a next-generation molecular manipulation aimed at inactivating Nr4a1 in a more precise manner. That study, published in the November 15, 2016, edition of Immunity, reports the loss of the same patrolling monocyte population following inactivation of a molecular switch that turns on Nr4a1. "This new work is exciting, because it shows that we can directly target genes within a specific cell type, which is important for targeted therapies," says Hedrick, a Professor in the Division of Inflammation Biology. The Hedrick laboratory's previous demonstration that patrolling monocytes disappear following global Nr4a1 loss proved that the gene is necessary for development of that cell type. Later, her group reported that cancer cells injected into mice lacking Nr4a1 (therefore lacking patrolling monocytes) underwent unchecked metastasis, supporting the idea that patrolling monocytes play anti-cancer roles. But an important experimental question lingered: could the cancer metastasis seen in Nr4a1 knockout mice have anything to do with potential loss of Nr4a1 in a closely related group of cells called macrophages, which use Nr4a1 to control inflammation? The new paper answers this question by silencing Nr4a1 only in patrolling monocytes. The Hedrick group accomplished this by applying good old-fashioned biochemistry to isolate stretches of DNA that flank the gene and define the on-switch for monocytes. Scientists call tissue-specific gene regulatory elements like this "enhancers." They then showed that when activated, that DNA region, which they called "enhancer #2" (E2), was capable of switching on Nr4a1 expression only in patrolling monocytes, and not in related cells like macrophages. The group proved the specificity of the enhancer by engineering mice whose genomes lacked only the E2 enhancer--not the gene itself--and indeed observed a lack of patrolling monocytes. "Until now, we did not have a way to delete a gene only in monocytes without also deleting it in macrophages," says Graham Thomas, Ph.D., a postdoc in the Hedrick lab and the study's first author. "Targeting the enhancer allows us to study particular cell types in a highly specific way," says Thomas. "Also, eliminating enhancers teaches us what turns these genes on in the first place. That knowledge is essential if we are going to design rational targets to go after these cells." To confirm that macrophages throw an entirely different molecular switch to turn on Nr4a1, the group exposed mice missing the monocyte E2 switch to a noxious toxin found in bacterial membranes, as a way of seeing whether macrophages can still mount normal inflammatory responses. Indeed, the macrophage response was entirely normal in E2 mutants, unlike the global Nr4a1 "knockout", showing that macrophages do not use the genetic E2 switch. Finally, to make sure that E2 enhancer loss mimicked deletion of the entire gene in monocytes the group revisited a tumor model previously used to test Nr4a1's anti-cancer effect. To do so, they injected melanoma cells into the bloodstream of normal or E2 mutant mice and monitored lung metastasis. Remarkably, outcomes following loss of the switch mirrored what the group had previously observed when they physically removed the gene itself: the lungs of mutant mice contained many more melanoma cells than did lungs of normal mice. This confirmed that the gene regulatory switch is highly specific to one cell type, monocytes and that tumor cell invasion in the absence of this population had nothing to do with deregulated macrophage activity. Hedrick also thinks the new findings provide new understanding of just how important DNA enhancer regions can be. "Being able to selectively target specific cell types opens up a new world for understanding how to design therapies to treat disease," she says. Also contributing from LJI were Richard Hanna, Ph.D., Amy Blatchley, Debbie Yoakum, Sara McArdle, Ph.D., and Zbigniew Mikulski, Ph.D. Other contributors include Neelakantan T. Vasudevan, PhD., and Mukesh Jain, M.D., from Case Western Reserve University in Cleveland; Casey Romanoski, PhD., from the University of Arizona; and Kevin Ross, Bruce Hamilton, Ph.D., and Chris Glass, PhD, all from UCSD. The study was funded by the National Institutes of Health (R01 HL118765, R01HL134236, R01 CA202987, and R01 GM086912; American Heart Association fellowships 16POST27630002and12DG12070005, and Ruth Kirschstein National Research Service Award (NRSA) and Institutional Predoctoral Training Grant, T32 GM008666, from the National Institute of General Medical Sciences. La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.


News Article | December 20, 2016
Site: www.eurekalert.org

LA JOLLA, CA--Aedes aegypti mosquitoes harboring parasitic Zika virus (ZIKV) are the primary transmitters of virus to humans, potentially causing catastrophic congenital microcephaly in babies born to women bitten by infected mosquitoes. But confirmation earlier this year by the Centers for Disease Control and Prevention (CDC) that ZIKV can also be sexually transmitted raised new alarm that virus could be passed between sexual partners in venues far from mosquito habitats. Now La Jolla Institute for Allergy & Immunology (LJI) investigator Sujan Shresta, Ph.D., employs two different mouse models to confirm that live ZIKV placed directly in the vagina infects the mouse's reproductive tract, replicates, moves into the bloodstream, and causes clinical signs of disease. Intriguingly, that study published in the December 20, 2016 issue of Cell Reports, also reports that the stage of the reproductive cycle during which a female mouse is exposed to virus determines vulnerability to infection. If applicable to humans, this discovery has public health implications for virus transmission to a population of great concern, women of child-bearing age. "Currently, almost all of our efforts in terms of Zika prevention focus on mosquito control," says Shresta, an associate professor in LJI's Center for Infectious Disease. "Our new work begs clinicians to also address whether sexual transmission of the virus constitutes a small or large proportion of cases." Investigators knew that virus hides in semen of men who contract ZIKV from mosquitoes and that virus is transmitted vaginally in rodent models. But the biological questions--what cells are infected, how stable the virus is in bodily fluids--were unanswered. Shresta's group began to explore them by placing live ZIKV in the vaginas of female mice that had been genetically engineered to be immunocompromised. But before the procedure, they treated mice with hormones to create two groups that differed with regard to where they were in their menstrual cycle. Dramatic differences emerged post-infection: mice infected in the diestrus or in between phase became progressively sick, lost weight, and died in 2-3 weeks, as one might predict in these mice. Remarkably, the same strain of immunocompromised AG129 mice infected in estrus phase showed no sign of disease. William Weihao Tang, the study's first author, calls this one the paper's most intriguing findings. "The strain of mice we used, called AG129, were originally engineered to be extremely vulnerable to infection," he says. "But even these mice, when infected in estrus phase, appeared completely resistant to virus. That surprised us." Shresta says that a caveat is that responses in mouse strains like AG129, which were purposely engineered to serve as a "lethal" model of infection, must be tested in mice with greater immune function. "For science to be relevant to humans, we always confirm results in the most 'immunocompetent' mouse that better reflects a normal human immune system." To do that, her team repeated experiments in an entirely different type of engineered mouse, one only moderately susceptible to infection, which scientists call a "non-lethal" model. When infected in diestrus phase, those mice lost weight and exhibited clinical signs of disease but, unlike their AG129 counterparts, eventually recovered. However, just like the AG129 mice, when infected in estrus phase "non-lethal" mice showed no sign of Zika-like disease. This trend was reflected in other experimental outcomes. For example, in both lethal and non-lethal strains, viral RNA, which serves as direct evidence of virus, persisted in the vaginal canal sometimes as long as 10 days post-infection in diestrus. By contrast, viral RNA disappeared three days after infection in estrus phase. Virus persistence in vaginal fluids may account for why diestrus-infected mice become sick, regardless of mouse strain, yet the molecular or cellular basis for susceptibility remains unclear. Mice analyzed in the study were experimentally synchronized or "staged" at one of two reproductive phases by hormonal injection, which may provide a clue. "Hormones changed the mouse female reproductive tract in ways that either enhanced or protected against sexual transmission," says Tang, although he and Shresta caution it is much too early to generalize mouse findings to humans. But if similar mechanisms prove relevant to human transmission, they are cause for concern, largely because most Zika-infected men or women show few or no symptoms. Thus they could unwittingly engage in sexual activity resulting in adult disease or even in utero transfer of virus to an unborn child. Recent CDC "case counts" suggest that thus far that few Zika cases in the US were likely transmitted sexually. But these numbers are estimates, and sexual transmission of ZIKV is taken extremely seriously in other regions, such as South America. In fact, one mathematical modeling study of Baranquilla, Colombia, estimated that as many as 47% of Zika cases reported there emerged from sexual contact. "In humans sexual transmission may be a bigger deal than has been thought," says Shresta, emphasizing that currently we know very little about this mode of Zika transmission. "We know that in males virus can remain in semen for possibly months, while a man shows no symptoms. During that time he could unknowingly pass it to a sexual partner." The next step for the Shresta lab is to take advantage of these two mouse models to define immune signals that make mice susceptible to or protected from ZIKV infection. "We are ultimately interested in drugs or vaccines to prevent the disease," says Shresta, who has also used immunodeficient mice as models to study dengue virus infection. "Being able to test interventions in two animal models, one that succumbs to infection and another that recovers, is a plus. Developing vaccines requires access to models representing all scenarios." Other contributors include Matthew Perry Young, Anila Mamidi, Jose Angel Regla-Nava, PhD, and Kenneth Kim, DVM, all from LJI. The study was funded by NIAID/NIH grant 1R01 AI116813 and by institutional support from the La Jolla Institute for Allergy and Immunology. La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.


News Article | December 7, 2016
Site: www.eurekalert.org

LA JOLLA, CA--The fate of stem cells is determined by series of choices that sequentially narrow their available options until stem cells' offspring have found their station and purpose in the body. Their decisions are guided in part by TET proteins rewriting the epigenome, the regulatory layer of chemical flags that adorn the genome and influence gene activity, report researchers at La Jolla Institute for Allergy and Immunology and UC San Diego. Publishing in this week's Early Edition of the Proceedings of the National Academy of Sciences, the study led by LJI professor Anjana Rao, Ph.D., details how TET proteins help stem cells strike the proper balance between developing into neural tissue or taking the heart and muscle route at an early and crucial intersection. "In particular, TET proteins are important to steer stem cells toward the neural lineage during early embryogenesis," says postdoctoral researcher and first author Xiang Li. "It confirmed what we had suspected--that TET proteins help drive early neurogenesis--but until now the formal proof had been missing." As a clearer picture of the molecular signals triggering certain cell fate decisions emerges, Li hopes that "it brings us closer to using stem cells to treat neuronal disease." TET proteins influence gene expression by specifically modifying methyl groups attached to cytosine, one of the four letters in DNA. Although these methyl group alterations are important in their own right, they also facilitate the complete removal of methyl groups from cytosine. While methylation and the enzymes required to add methyl groups have been extensively studied as a fundamental force that that helps guide stem cells toward their future lineage during embryonic development, much less is known about the reverse process. "During early embryogenesis waves of demethylation sweep the genome but we haven't really understood what the relevance is," senior author Sylvia Evans, Ph.D., a professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, who collaborated with Rao's team. "By creating triple knockouts that miss all three genes coding for TET proteins and studying them, in vivo, we have learned that yes, the dynamic modulation of the methylation status is critically important for driving developmental gene expression programs in the early embryo." Li started his investigations with mouse embryonic stem cells (mES) deficient for Tet3 only, or deficient for all three members (Tet1/2/3) of the Tet protein family. During differentiation, cell types from both mouse strains steered clear from committing to the neuroectodermal lineage, which goes on to form the brain and spinal cord and is considered the "default" pathway for mECs cultured under certain culture conditions. A genome-wide analysis revealed that Tet3 exerts its effect through the inhibition of Wnt-signaling. Wnt signalling is necessary for the proper formation of heart and muscle. "Without Tet3, Wnt signaling is no longer suppressed and can push differentiating stem cells toward a mesodermal cell fate," explains Li. The mesoderm develops into connective tissue, muscle, bone, as well as the urogenital and circulatory system including the heart. The results from lab-grown mECs prompted the researchers to look for developmental abnormalities in Tet3 and Tet1/2/3-deficient mice. The Tet3 knock-out showed no overt cardiac or neuronal abnormalities, which pointed to functional redundancies between different Tet family members. Tet1/2/3-deficient mice, however, had major defects in neural development, confirming a key role for TET proteins in guiding stem cells down the right path. The work was partly funded by NIH R01 grants CA151535 and HD065812 and the CIRM UCSD Interdisciplinary Stem Cell Research & Training Grant II (TG2-01154). Full citation: "TET proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling." Xiang Li, Xiaojing Yue, William A. Pastor, Lizhu Lin, Romain Georges, Lukas Chavez, Sylvia M. Evans, Anjana Rao. PNAS 2016. doi:10.1073/pnas.1617802113 La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.


Huang Y.,La Jolla Institute | Huang Y.,Texas A&M University | Rao A.,La Jolla Institute
Trends in Genetics | Year: 2014

DNA methylation has been linked to aberrant silencing of tumor suppressor genes in cancer, and an imbalance in DNA methylation-demethylation cycles is intimately implicated in the onset and progression of tumors. Ten-eleven translocation (TET) proteins are Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases that successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thereby mediating active DNA demethylation. In this review, we focus on the pathophysiological role of TET proteins and 5hmC in cancer. We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-. N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer. © 2014 Elsevier Ltd.


Gillies L.A.,La Jolla Institute | Kuwana T.,La Jolla Institute
Journal of Cellular Biochemistry | Year: 2014

Mitochondria play a critical role in apoptosis, or programmed cell death, by releasing apoptogenic factors from the intermembrane space. This process, known as mitochondrial outer membrane permeabilization (MOMP), is tightly regulated by the Bcl-2 family proteins. Pro-apoptotic Bcl-2 family members, Bax and Bak, change their conformation when activated by BH3 domain-only proteins in the family and permeabilize the MOM, whereas pro-survival members inhibit permeabilization. The precise nature of the apoptotic pore in the MOM is unknown, but is probably lipidic. Furthermore, it has been realized that there is another layer of MOMP regulation by a protein factor termed the catalyst in the MOM in order for Bax/Bak to achieve efficient and complete membrane permeabilization. Mitochondrial dynamics do not affect MOMP directly, but seem closely coordinated with MOMP for swift protein efflux from mitochondria. This review will present current views on the molecular mechanisms and regulation of MOMP and conclude with recent developments in clinical applications based on the knowledge gleaned from the investigation. J. Cell. Biochem. 115: 632-640, 2014. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

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