Albert Sherman Center
Albert Sherman Center
Megaw R.,University of Edinburgh |
Abu-Arafeh H.,University of Edinburgh |
Jungnickel M.,University of Edinburgh |
Mellough C.,Newcastle University |
And 9 more authors.
Nature Communications | Year: 2017
Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP. © 2017 The Author(s).
News Article | February 15, 2017
WORCESTER, MA - A father's nicotine use may have a significant impact on children's risk of some diseases. In a study published in the online biomedical sciences journal eLife, Oliver J. Rando, MD, PhD, and colleagues at UMass Medical School, demonstrate that mice born of fathers who are habitually exposed to nicotine inherit enhanced chemical tolerance and drug clearance abilities. These findings offer a powerful framework for exploring how information about a father's environmental exposure history is passed down to offspring. "Children born of fathers who have been exposed to nicotine are programmed to be not only more resistant to nicotine toxicity, but to other chemicals as well," said Dr. Rando, professor of biochemistry & molecular pharmacology. "If a similar phenomenon occurs in humans, this raises many important questions. For example, if your father smoked does that mean chemotherapy might be less effective for you? Are you more or less likely to smoke? It's important to understand what information is specifically being passed down from father to offspring and how that impacts us." Studies over the past decade in the field of epigenetics - the study of inheritable traits that are carried outside the genome - have provided unexpected support to the notion that the environmental conditions experienced by a parent can affect disease risk and other features of future generations. In mammals, many of these studies have focused on interactions between the male parent and the offspring - paternal effects - as these are in many ways easier to investigate than maternal effects. Specifically, a number of studies have linked paternal diet to metabolic changes in offspring, while others link paternal stress to anxiety-like behaviors in the next generation. Despite the growing number of these studies, only a small number of paternal exposures have been explored rigorously in the lab. In addition, it has remained unclear in these studies whether the offspring response is specific for the paternal exposure, or whether it is a more generic response to a father's overall quality of life. To address this question, Rando and colleagues set out to determine how precise the response is for the environment experienced by the male parent, by looking at a single molecular interaction. Nicotine is a commonly used drug in humans, and acts by binding to a specific molecular receptor. Providing male mice with access to nicotine, researchers sought to learn whether their offspring were more or less sensitive to nicotine, and whether the offspring response was specific to nicotine or extended to other molecules. What researchers found is that the offspring of nicotine-exposed fathers, compared to the offspring of fathers that were never exposed to nicotine, were protected from toxic levels of nicotine. Researchers then tested whether this resistance was specific for nicotine by treating both sets of offspring with cocaine, which acts via a wholly distinct molecular pathway than nicotine. Surprisingly, the children of nicotine-exposed fathers were also protected from cocaine. This multi-toxin resistance is likely a result of enhanced drug metabolism in the liver, and corresponds to an increase in expression levels of genes involved in drug metabolism. These genes were also packaged in a more open and accessible configuration in the liver cells, allowing for increased expression. "This demonstrates that 'dad' paints with very broad brush strokes. Fathers exposed to nicotine do not specifically program changes in nicotine receptors in their children, as these children are broadly resistant to multiple toxins," said Rando. To determine if multiple, distinct molecules are capable of affecting drug resistance in the next generation, Rando and colleagues treated male mice with another bioactive compound, mecamylamine, which blocks nicotine receptors and is sometimes used to help people stop smoking. Surprisingly, offspring of these mice exhibited the same chemical resistance as those exposed to nicotine. "These findings raise key questions about what drugs or molecules are sufficient to affect children of exposed fathers," said Rando. "What distinguishes nicotine and mecamylamine from the countless small molecules present in our food and environment?" The next step for Rando and colleagues is to determine how many channels of information are being passed down from parent to offspring. "We now know that this information is relatively nonspecific," he said. "But is dad only telling us, on a scale of 1 to 10, that his life was good or not, or is he telling us four or five things broadly about the amount of food, level of stress and degree of chemical exposure?" Given the prevalence of smoking in humans, Rando notes that "there are obvious reasons to be interested in whether this type of effect also happens in human beings, but given the differences between mice and humans in their metabolism of nicotine, it will need to be tested rigorously in future studies of human populations." The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, is comprised of the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the Commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $266 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.
News Article | December 5, 2016
WORCESTER: UMass Medical School scientist Gang Han, PhD, and his team have designed a new class of molecules used in photodynamic therapy that are able to direct lamp light deep into tissue to kill cancer tumors. In a new paper published in the Journal of the American Chemical Society, Dr. Han, associate professor of biochemistry & molecular pharmacology, outlines how the carbazole-substituted BODIPY (Car-BDP) molecules, which possess an intense, broad NIR absorption band with a remarkably high singlet oxygen quantum yield, will further the potential clinical application for photodynamic therapy. "This study signals a major step forward in photodynamic therapy by developing a new class of NIR-absorbing biodegradable organic nanoparticles for a highly effective targeting and treatment of deep-tissue tumors," Han said. Tissue penetration depth is a major challenge in practical photodynamic therapy. Traditionally, it involves the patient receiving a nontoxic light-sensitive drug, which is absorbed by all the body's cells, including cancerous ones. A red laser light specifically tuned to the drug molecules is then selectively turned on in the tumor area. When the red light interacts with the photosensitive drug, it produces a highly reactive form of oxygen (singlet oxygen) that kills the malignant cancer cells while leaving most neighboring cells unharmed. Based on research by the Han Lab at UMMS and colleagues, the process might become simpler, more effective and cost efficient. Han explained that after being encapsulated with biodegradable polymers, Car-BDP molecules can form uniform and small, organic nanoparticles that are water-soluble and tumor targetable. Used in conjunction with a record low-power-density and cost-effective incoherent lamp light, rather than the coherent high power laser light that is used in the existing therapy, the molecules can be tracked as they spread through the body, deep into the tissue and to outline and kill cancerous tumors. More interestingly, the organic nanoparticles were found to have an extremely long circulating time and can be removed from body, which is essential for new practical photodynamic therapy drug development, Han said. Han said the combination is "sufficient to monitor and trigger practical photodynamic therapy effect of these nanoparticles within a wide variety of deep-tissue level tumors such as lung, colon, prostate and breast cancers." In addition, the potential new platform for precise tumor-targeting theranostics and novel opportunities with low power lamp light could allow for future affordable clinical cancer treatment that patients may be able to manage in their homes or resource deficient areas, such as on battlefields and in developing countries. The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, comprises the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $240 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.
Wahl I.,University of Hamburg |
Lowe B.,University of Hamburg |
Bjorner J.B.,Copenhagen University |
Fischer F.,Charité - Medical University of Berlin |
And 9 more authors.
Journal of Clinical Epidemiology | Year: 2014
Objectives To provide a standardized metric for the assessment of depression severity to enable comparability among results of established depression measures. Study Design and Setting A common metric for 11 depression questionnaires was developed applying item response theory (IRT) methods. Data of 33,844 adults were used for secondary analysis including routine assessments of 23,817 in- and outpatients with mental and/or medical conditions (46% with depressive disorders) and a general population sample of 10,027 randomly selected participants from three representative German household surveys. Results A standardized metric for depression severity was defined by 143 items, and scores were normed to a general population mean of 50 (standard deviation = 10) for easy interpretability. It covers the entire range of depression severity assessed by established instruments. The metric allows comparisons among included measures. Large differences were found in their measurement precision and range, providing a rationale for instrument selection. Published scale-specific threshold scores of depression severity showed remarkable consistencies across different questionnaires. Conclusion An IRT-based instrument-independent metric for depression severity enables direct comparisons among established measures. The "common ruler" simplifies the interpretation of depression assessment by identifying key thresholds for clinical and epidemiologic decision making and facilitates integrative psychometric research across studies, including meta-analysis. © 2014 Elsevier Inc. All rights reserved.
Maranda L.,Albert Sherman Center |
Gupta O.T.,University of Texas Southwestern Medical Center
PLoS ONE | Year: 2016
Type 1 diabetes mellitus (T1DM) a chronic characterized by an absolute insulin deficiency requires conscientious patient self-management to maintain glucose control within a normal range. Family cohesion and adaptability, positive coping strategies, social support and adequate self-regulatory behavior are found to favorably influence glycemic control. Our hypothesis was that the responsible care of a companion animal is associated with these positive attributes and correlated with the successful management of a chronic illness such as type 1 diabetes. We recruited 223 youths between 9 and 19 years of age from the Pediatric Diabetes clinic at the University of Massachusetts Medical School, reviewed the status of their glycemic control (using three consecutive A1c values) and asked them questions about the presence of a pet at home, and their level of involvement with its care. Multivariate analyses show that children who care actively for one or more pets at home are 2.5 times more likely to have control over their glycemic levels than children who do not care for a pet, adjusting for duration of disease, socio-economic status, age and self-management [1.1 to 5.8], pWald = 0.032. A separate model involving the care of a petdog only yielded comparable results (ORa = 2.6 [1.1 to 5.9], pWald = 0.023). © 2016 Maranda, Gupta. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Liu L.,Albert Sherman Center |
Nam M.,Albert Sherman Center |
Fan W.,Albert Sherman Center |
Akie T.E.,Albert Sherman Center |
And 4 more authors.
Journal of Clinical Investigation | Year: 2014
Sirtuin 3 (SIRT3), an important regulator of energy metabolism and lipid oxidation, is induced in fasted liver mitochondria and implicated in metabolic syndrome. In fasted liver, SIRT3-mediated increases in substrate flux depend on oxidative phosphorylation (OXPHOS), but precisely how OXPHOS meets the challenge of increased substrate oxidation in fasted liver remains unclear. Here, we show that liver mitochondria in fasting mice adapt to the demand of increased substrate oxidation by increasing their OXPHOS efficiency. In response to cAMP signaling, SIRT3 deacetylated and activated leucine-rich protein 130 (LRP130; official symbol, LRPPRC), promoting a mitochondrial transcriptional program that enhanced hepatic OXPHOS. Using mass spectrometry, we identified SIRT3-regulated lysine residues in LRP130 that generated a lysine-to-arginine (KR) mutant of LRP130 that mimics deacetylated protein. Compared with wild-type LRP130 protein, expression of the KR mutant increased mitochondrial transcription and OXPHOS in vitro. Indeed, even when SIRT3 activity was abolished, activation of mitochondrial transcription and OXPHOS by the KR mutant remained robust, further highlighting the contribution of LRP130 deacetylation to increased OXPHOS in fasted liver. These data establish a link between nutrient sensing and mitochondrial transcription that regulates OXPHOS in fasted liver and may explain how fasted liver adapts to increased substrate oxidation. © Copyright 2014 American Society for Clinical Investigation.
Lewandowski S.L.,University of Massachusetts Medical School |
Janardhan H.P.,University of Massachusetts Medical School |
Trivedi C.M.,University of Massachusetts Medical School |
Trivedi C.M.,Albert Sherman Center
Journal of Biological Chemistry | Year: 2015
Background: Histone-modifying genes play critical roles in the pathogenesis of human congenital heart disease. Results: HDAC3 recruits PRC2 complex to mediate epigenetic silencing of TGF-β1 in a deacetylase-independent manner within second heart field progenitor cells. Conclusion: HDAC3-mediated epigenetic silencing of TGF-β1 is required for normal heart development. Significance: This is the first report of HDAC-mediated epigenetic regulation of second heart field development. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.