California National Primate Research Center

Davis, CA, United States

California National Primate Research Center

Davis, CA, United States

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News Article | May 3, 2017
Site: www.futurity.org

A new study shows that gene editing using CRISPR/Cas9 technology can work in rhesus monkey embryos. The results, published in the current issue of Human Molecular Genetics, open the door for pursuing gene editing in nonhuman primates as models for new therapies, including pharmacological, gene-, and stem cell-based therapies, says Keith Latham, animal science professor at Michigan State University and lead author of the study. “Our paper is the first in the US to publish on the use of this technology in nonhuman primate embryos,” he says. “Using nonhuman primate embryos is important because the closer we can approximate the human condition in the animal model, the better the chances of developing successful treatments as well as limiting risks that may be encountered in clinical trials.” While mice are mammals, they bear litters rather than individual offspring. Their anatomy and physiology differ in many respects from humans. While many advances in understanding diseases have been made first using mouse models, making the leap from a successful mouse study to clinical trials can be difficult or impossible for some areas of research. “If scientists want to test drugs for dementia, Alzheimer’s, or autism, ideal models would react similarly to humans in regards to the reduction of symptoms, outbreak of side effects, such as enduring the same lesions as humans do, or exhibiting similar behavioral characteristics,” says Latham. “Nonhuman primates are much better models for such diseases. And in terms of some surgical procedures, implants, developing prosthetics, or other therapies, nonhuman primates can prove better suited than rodents.” CRISPR has opened the door to do gene editing in many species other than mice. Developing this technology in nonhuman primates in the US would allow more scientists in this country to incorporate these models into their research, he adds. The advances will allow scientists to move forward and tackle some of the technical barriers related to the research. Other issues that may be later resolved are the commitment to increased costs and longer waiting times when using nonhuman primates. Fruit flies, often used in genetic studies, reproduce in two weeks. Rodents, with pre-disposed genetic characteristics, can be easily ordered and shipped to laboratories within days. Committing to raising nonhuman primates can cost around $15,000 and can take as long as four-to-six years to have a mature monkey with the desired genetic characteristics. The high-efficiency of gene editing that scientists are now able to achieve makes it worth the cost and the wait, Latham says. To conduct the research, Latham worked with the California National Primate Research Center, where the monkey embryos were produced, in collaboration with his co-investigator Catherine VandeVoort, an expert in nonhuman primate reproduction. Daniel Bauer, at Harvard Medical School, Boston Children’s Hospital, and Dana-Farber Cancer Institute also collaborated on the study. “Extreme amounts of care go into maintaining the well-being of the monkeys,” says Latham. “They follow strict protocols to ensure this is a priority. Funding came from the National Institutes of Health, Michigan State’s AgBioResearch, Michigan State, the National Institute of Diabetes and Digestive and Kidney Disease, the Burroughs Wellcome Fund, American Society of Hematology, Charles H. Hood Foundation, and Cooley’s Anemia Foundation.


News Article | May 1, 2017
Site: www.eurekalert.org

EAST LANSING, Mich. - Mice have been and will continue to be good base models for human medicinal advances. However, their size and some of their physiological differences leave them lacking in important areas of human medicine, including neurological and reproductive research. In a study led by Michigan State University, scientists have shown that gene editing using CRISPR/Cas9 technology can be quite effective in rhesus monkey embryos ¬- the first time this has been demonstrated in the U.S. The results, published in the current issue of Human Molecular Genetics, open the door for pursuing gene editing in nonhuman primates as models for new therapies, including pharmacological, gene- and stem cell-based therapies, said Keith Latham, MSU animal science professor and lead author of the study. "Our paper is the first in the U.S. to publish on the use of this technology in nonhuman primate embryos," he said. "Using nonhuman primate embryos is important because the closer we can approximate the human condition in the animal model, the better the chances of developing successful treatments as well as limiting risks that may be encountered in clinical trials." While mice are mammals, they bear litters rather than individual offspring. Their anatomy and physiology differ in many respects from humans. While many advances in understanding diseases have been made first using mouse models, making the leap from a successful mouse study to clinical trials can be difficult or impossible for some areas of research. "If scientists want to test drugs for dementia, Alzheimer's or autism, ideal models would react similarly to humans in regards to the reduction of symptoms, outbreak of side effects, such as enduring the same lesions as humans do, or exhibiting similar behavioral characteristics," said Latham, who's with the College of Agriculture and Natural Resources and an MSU AgBioResearch scientist. "Nonhuman primates are much better models for such diseases. And in terms of some surgical procedures, implants, developing prosthetics, or other therapies, nonhuman primates can prove better suited than rodents." CRISPR has opened the door to do gene editing in many species other than mice. Developing this technology in nonhuman primates in the U.S. would allow more scientists in this country to incorporate these models into their research, he added. The advances will allow scientists to move forward and tackle some of the technical barriers related to the research. Other issues that may be later resolved are the commitment to increased costs and longer waiting times when using nonhuman primates. Fruit flies, often used in genetic studies, reproduce in two weeks. Rodents, with pre-disposed genetic characteristics, can be easily ordered and shipped to laboratories within days. Committing to raising nonhuman primates can cost around $15,000 and can take as long as 4-6 years to have a mature monkey with the desired genetic characteristics. The high-efficiency of gene editing that scientists are now able to achieve makes it worth the cost and the wait, Latham said. To conduct the research, Latham partnered with the California National Primate Research Center, where the monkey embryos were produced, in collaboration with his co-investigator Dr. Catherine VandeVoort, an expert in nonhuman primate reproduction. Dr. Daniel Bauer, at Harvard Medical School, Boston Children's Hospital and Dana-Farber Cancer Institute also collaborated on the study. The resources offered by the CNPRC were crucial for this work, Latham said. "Extreme amounts of care go into maintaining the well-being of the monkeys," he said. "They follow strict protocols to ensure this is a priority. So being able to conduct the science here at Michigan State while partnering with the center is the best combination of science and animal welfare." Additional MSU scientists contributing to the study include Uros Midic, Kailey Vincent and Benjamin Goheen. This research was funded by the National Institutes of Health, MSU AgBioResearch, MSU, the National Institute of Diabetes and Digestive and Kidney Disease, the Burroughs Wellcome Fund, American Society of Hematology, Charles H. Hood Foundation and Cooley's Anemia Foundation. Michigan State University has been working to advance the common good in uncommon ways for more than 150 years. One of the top research universities in the world, MSU focuses its vast resources on creating solutions to some of the world's most pressing challenges, while providing life-changing opportunities to a diverse and inclusive academic community through more than 200 programs of study in 17 degree-granting colleges. For MSU news on the Web, go to MSUToday. Follow MSU News on Twitter at twitter.com/MSUnews.


News Article | May 1, 2017
Site: www.chromatographytechniques.com

Mice have been and will continue to be good base models for human medicinal advances. However, their size and some of their physiological differences leave them lacking in important areas of human medicine, including neurological and reproductive research. In a study led by Michigan State University, scientists have shown that gene editing using CRISPR/Cas9 technology can be quite effective in rhesus monkey embryos ­– the first time this has been demonstrated in the U.S. The results, published in the current issue of Human Molecular Genetics, open the door for pursuing gene editing in nonhuman primates as models for new therapies, including pharmacological, gene- and stem cell-based therapies, said Keith Latham, MSU animal science professor and lead author of the study. “Our paper is the first in the U.S. to publish on the use of this technology in nonhuman primate embryos,” he said. “Using nonhuman primate embryos is important because the closer we can approximate the human condition in the animal model, the better the chances of developing successful treatments as well as limiting risks that may be encountered in clinical trials.” While mice are mammals, they bear litters rather than individual offspring. Their anatomy and physiology differ in many respects from humans. While many advances in understanding diseases have been made first using mouse models, making the leap from a successful mouse study to clinical trials can be difficult or impossible for some areas of research. “If scientists want to test drugs for dementia, Alzheimer’s or autism, ideal models would react similarly to humans in regards to the reduction of symptoms, outbreak of side effects, such as enduring the same lesions as humans do, or exhibiting similar behavioral characteristics,” said Latham, who’s with the College of Agriculture and Natural Resources and an MSU AgBioResearch scientist. “Nonhuman primates are much better models for such diseases. And in terms of some surgical procedures, implants, developing prosthetics, or other therapies, nonhuman primates can prove better suited than rodents.” CRISPR has opened the door to do gene editing in many species other than mice. Developing this technology in nonhuman primates in the U.S. would allow more scientists in this country to incorporate these models into their research, he added. The advances will allow scientists to move forward and tackle some of the technical barriers related to the research. Other issues that may be later resolved are the commitment to increased costs and longer waiting times when using nonhuman primates. Fruit flies, often used in genetic studies, reproduce in two weeks. Rodents, with pre-disposed genetic characteristics, can be easily ordered and shipped to laboratories within days. Committing to raising nonhuman primates can cost around $15,000 and can take as long as four to six years to have a mature monkey with the desired genetic characteristics. The high-efficiency of gene editing that scientists are now able to achieve makes it worth the cost and the wait, Latham said. To conduct the research, Latham partnered with the California National Primate Research Center, where the monkey embryos were produced, in collaboration with his co-investigator Catherine VandeVoort, an expert in nonhuman primate reproduction. Daniel Bauer, at Harvard Medical School, Boston Children’s Hospital and Dana-Farber Cancer Institute also collaborated on the study. The resources offered by the CNPRC were crucial for this work, Latham said. “Extreme amounts of care go into maintaining the well-being of the monkeys,” he said. “They follow strict protocols to ensure this is a priority. So being able to conduct the science here at Michigan State while partnering with the center is the best combination of science and animal welfare.”


Engle J.R.,University of Arizona | Engle J.R.,California National Primate Research Center | Barnes C.A.,University of Arizona | Barnes C.A.,California National Primate Research Center
Frontiers in Aging Neuroscience | Year: 2012

An overview is provided of the simple single-cue delay and trace eyeblink conditioning paradigms as techniques to assess associative learning and memory in the aged. We highlight and focus this review on the optimization of the parameter space of eyeblink conditioning designs in the aged to avoid and control for potential confounds that may arise when studying aged mammals. The need to examine the contribution of non-associative factors that can contribute to performance outcomes is emphasized, and how age-related changes in the central nervous system as well as peripheral sensory factors can potentially bias the interpretation of the data in the aged is discussed. The way in which slight alterations of the parameter space in the delay and trace eyeblink conditioning paradigms can lead to delayed but intact conditioning, rather than impaired performance in aged animals is also discussed. Overall, the eyeblink conditioning paradigm, when optimized for the age of the animal in the study, is an elegantly simple technique for assessment of associative learning and memory. When design caveats described above are taken into account, this important type of memory, with its well-defined neural substrates, should definitely be included in cognitive assessment batteries for the aged. © 2012 Engle and Barnes.


Broadhurst M.J.,University of California at San Francisco | Ardeshir A.,California National Primate Research Center | Kanwar B.,University of California at San Francisco | Mirpuri J.,University of Texas Southwestern Medical Center | And 9 more authors.
PLoS Pathogens | Year: 2012

Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated. © 2012 Broadhurst et al.


Maninger N.,University of California at San Francisco | Maninger N.,California National Primate Research Center | Capitanio J.P.,California National Primate Research Center | Mason W.A.,California National Primate Research Center | And 2 more authors.
Psychoneuroendocrinology | Year: 2010

Most studies on the stress-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis have focused on glucocorticoids, while few studies have investigated the adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), which is unique to primates. Monkeys were chair-restrained for 2. h per day for seven consecutive days, and blood samples were collected upon placement in the chair, and at 15, 30, 60 and 120. min later. Like cortisol, DHEAS concentrations increased throughout the initial session of chair restraint (acute stress). Unlike the cortisol response, which decreased after repeated exposure to the stressor, the DHEAS response was sustained throughout the seventh session of restraint (chronic stress) and response to the seventh session of restraint did not differ from the DHEAS response to the initial session. Like cortisol, DHEAS concentrations showed a diurnal rhythm with higher concentrations in the morning compared to the evening and a decrease in response to dexamethasone (DEX) administration. After repeated exposure to the stressor, the suppression of DHEAS in response to dexamethasone was more complete, suggesting an increase in negative feedback sensitivity. These data show that DHEAS concentrations increase in response to both acute and chronic (repeated) stress and provide another measure of HPA activity that parallels cortisol during acute responses to stress but diverges in chronic or repeated stress. © 2010.


Machado C.J.,University of California | Machado C.J.,California National Primate Research Center | Whitaker A.M.,University of California | Whitaker A.M.,California National Primate Research Center | And 4 more authors.
Biological Psychiatry | Year: 2015

Background Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions. Methods We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study. Results As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images. Conclusions In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia. © 2015 Society of Biological Psychiatry.


VandeVoort C.A.,California National Primate Research Center | VandeVoort C.A.,University of California at Davis | Hill D.L.,California National Primate Research Center | Chaffin C.L.,University of Maryland Baltimore County | Conley A.J.,University of California at Davis
Alcoholism: Clinical and Experimental Research | Year: 2011

Background: The timing of the origins of fetal alcohol syndrome has been difficult to determine, in part because of the challenge associated with in vivo studies of the peri-implantation stage of embryonic development. Because embryonic stem cells (ESCs) are derived from blastocyst stage embryos, they are used as a model for early embryo development. Methods: Rhesus monkey ESC lines (ORMES-6 and ORMES-7) were treated with 0, 0.01, 0.1, or 1.0% ethanol, 1.0% ethanol with estradiol, or 0.00025% acetaldehyde with or without estradiol for 4weeks. Results: Although control ESCs remained unchanged, abnormal morphology of ESCs in the ethanol and acetaldehyde treatment groups was observed before 2weeks of treatment. Immunofluorescence staining of key pluripotency markers (TRA-1-81 and alkaline phosphatase) indicated a loss of ESC pluripotency in the 1.0% ethanol group. ORMES-7 was more sensitive to effects of ethanol than ORMES-6. Conclusions: Estradiol appeared to increase sensitivity to ethanol in the ORMES-6 and ORMES-7 cell line. The morphological changes and labeling for pluripotency, proliferation, and apoptosis demonstrated that how ethanol affects these early cells that develop in culture, their differentiation state in particular. The effects of ethanol may be mediated in part through metabolic pathways regulating acetaldehyde formation, and while potentially accentuated by estradiol in some individuals, how remains to be determined. © 2011 by the Research Society on Alcoholism.


Bales K.L.,University of California at Davis | Bales K.L.,California National Primate Research Center | Saltzman W.,University of California at Riverside
Hormones and Behavior | Year: 2016

This article is part of a Special Issue "Parental Care". Paternal care, though rare among mammals, is routinely displayed by several species of rodents. Here we review the neuroanatomical and hormonal bases of paternal behavior, as well as the behavioral and neuroendocrine consequences of paternal behavior for offspring. Fathering behavior is subserved by many of the same neural substrates which are also involved in maternal behavior (for example, the medial preoptic area of the hypothalamus). While gonadal hormones such as testosterone, estrogen, and progesterone, as well as hypothalamic neuropeptides such as oxytocin and vasopressin, and the pituitary hormone prolactin, are implicated in the activation of paternal behavior, there are significant gaps in our knowledge of their actions, as well as pronounced differences between species. Removal of the father in biparental species has long-lasting effects on behavior, as well as on these same neuroendocrine systems, in offspring. Finally, individual differences in paternal behavior can have similarly long-lasting, if more subtle, effects on offspring behavior. Future studies should examine similar outcome measures in multiple species, including both biparental species and closely related uniparental species. Careful phylogenetic analyses of the neuroendocrine systems presumably important to male parenting, as well as their patterns of gene expression, will also be important in establishing the next generation of hypotheses regarding the regulation of male parenting behavior. © 2015 Elsevier Inc.


The male contraceptive gel Vasalgel was shown effective in preventing pregnancies in trials conducted on a group of rhesus monkeys. Results of the trial, which was published in Basic and Clinical Andrology on Feb. 7, showed that despite typically high pregnancy rates of about 80 percent in female monkeys housed with males, no pregnancy occurred over the study period covering at least one breeding season when the males were treated with the contraceptive gel. The findings offer hope for a new birth control method that men can use. If proven effective and safe enough for humans, Vasalgel could be an alternative for vasectomy. "One of the great things about the monkey model is that the male reproductive tract is very similar to humans and they have even more sperm than humans do," said Catherine VandeVoort, from the California National Primate Research Center. "Chances are, it's going to be effective in humans." Withdrawal method and condoms are currently the best option for these men but withdrawal method poses high pregnancy risk and condoms can disrupt spontaneity during sexual contact. Although vasectomy is highly effective, it is poorly reversible, which means it is not the best option for those who need temporary protection. Based on earlier trials involving rabbits, Vasalgel could be a sort of a reversible vasectomy albeit results of animal studies still need to be replicated in humans. While other studies are also being conducted to develop a male hormonal contraceptive that can be as effective as the birth control pills taken by women, scientists are concerned over the unwanted side effects of these types treatment which include depression and soaring libido. The Vasalgel though does not interfere with the production of sperm nor changes the hormone levels in the body, which means that the side effects seen in hormone-altering pills, gels, and injections would not be an issue. While VandeVoort and colleagues reported that use of Vasalgel was well tolerated in monkey subjects, there are still issues and complications that arose due to use of the contraceptive gel. The researchers, for instance, inserted the gel into one of the 16 monkeys involved in the trial incorrectly. "Complications during Vasalgel placement in one animal (Animal 3) were associated with damage to the wall of the vas deferens, likely as a result of incorrect placement of the catheter, resulting in incomplete penetration of the wall of the vas deferens," the study researchers wrote in their study. "This resulted in extraluminal leakage of Vasalgel within the thin fibrous sheath surrounding the vas, likely weakening the overall structure." Another subject also developed sperm granuloma. The condition, which is caused by leaking sperm, is characterized by a lump of sperm forming at the site where the vas deferens, the tube that carries the sperm from the testes to the penis, is tied off. Granuloma commonly occurs after vasectomy. Inflammation, which also commonly occurs after vasectomy, however, was minimal with Vasalgel. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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