About the Pilot Research Program
The CNPRC Pilot Research Program provides an administrative mechanism by which Principal Investigators in any discipline, and particularly those that are not closely related to the Center’s categorical Research Units, may have full opportunity to use the Center’s resources. This program serves as a resource to the entire biomedical research community, including regional, national and international researchers. The objectives of the program are to provide resources (including Core Scientist expertise) and facilities for primate research to Principal Investigators who are not CNPRC Core Scientists, and to provide the expertise to affiliates in all facets of the on-site portion of primate research.
Pilot research projects are to be used for generating preliminary data for submission of NIH grant proposals, with the goal of supporting new, extramurally-funded research utilizing nonhuman primate models of human disease. Proposals to the highly competitive program are evaluated for scientific merit (significance, approach, innovation) and likelihood of the project leading to a successful NIH grant application.
2019-2020 Pilot Research Program Recipients
“Metacognitive awareness for memory in aging: a rhesus macaque model.” In addition to memory loss in aging and Alzheimer’s disease, many individuals also lack awareness that their memory is declining. Lack of awareness is associated with poorer treatment outcomes and increased healthcare costs. This project tests a monkey model of memory awareness and aging, with the goals of identifying biomarkers of impaired memory awareness and ultimately linking them to aging related neuropathology.
“Developing silicone oil-induced reversible ocular hypertension glaucoma model in aged rhesus monkeys.”Glaucoma is the most common cause of irreversible blindness and elevated intraocular pressure and aging are the two known risk factors. There is an urgent need to develop a simple, reliable, and, most importantly, reversible experimental ocular hypertension/glaucoma model in a species that can closely resemble human glaucoma. The anatomy of the nonhuman primate (NHP) visual system closely resembles the human and an aged NHP glaucoma model is the most likely to predict human responses to ocular hypertension, aging and therapies. We propose to adapt our successful mouse silicone oil-induced reversible ocular hypertension model into a novel NHP glaucoma model, which is essential for translating novel strategies into efficient treatment for glaucoma patients.
“IL-10 driven suppression of vaccine responsiveness in aged macaques.” Age-related inflammation (so-called inflammaging) is associated with many deleterious processes in the elderly, including Alzheimer’s disease, cardiovascular disease, and general frailty. Declining immune function is well described in the elderly, and leads to increased risk and severity of infection, poorer control of cancer, and impaired responses to vaccination. Our long-term goal is to develop therapeutic strategies to enhance protective immune responses in the elderly. Here, we propose to determine if short-term IL-10 blockade will restore flu vaccine responsiveness in aged macaques.
“Materials-based cell selection from bone marrow aspirates from the elderly for robust osteogenic grafts.” Bone fractures are one of the most significant clinical problems for the elderly. Autologous cell-based therapies are a promising alternative to bone grafts, which are limited for the elderly, but suffer from reduced availability, rapid death upon transplantation, and insufficient instructional cues to guide bone formation at the defect site. Cell-secreted extracellular matrix, produced by multipotent progenitor cells, increase cell adhesion, survival, and provide necessary instructional cues to transplanted cells to form bone. In these studies, we will test the effect of donor age on extracellular matrix production and its ability to instruct bone-forming cells from aged donors. The results of these studies will provide new insight into methods to encourage bone formation using cells from older donors.
“Characterizing the sex-specific mutation rate in titi monkeys.” Mutation is the ultimate source of heritable variation in the genome and thus essential for the process of evolution. Importantly, mutation is not a homogeneous process and substantial variation exists in both mutation rates as well as mutational spectra between primate species, influenced by a variety of genetic factors, evolutionary processes, and life history traits. This project will estimate the spontaneous mutation rate for titi monkeys (Callicebus cupreus) – a member of the New World monkey family which has not yet been genetically characterized – to illuminate existing variation in mutation rates between primate species and their correlation with different genomic and non-genomic factors. The generated genomic resources will not only allow us to define the time-scale and magnitude at which this parameter has evolved across primates but it will also represent a valuable resource for future biodevelopmental and biomedical research.
2018-2019 Pilot Research Program Recipients
“Inflammatory and organ injury effects of daily e-cigarette use.” The recent tripling of e-cigarette use by children in the U.S. poses a new public health threat, as e-cigarettes both have largely unknown chronic cardiopulmonary effects and provide a gateway to smoking conventional cigarettes, a major cause of preventable harm. This work will assess potential toxicities of e-cigarette use on lung, kidney, liver and immune system functions in mammals most closely related to humans – non-human primates. This work will also provide first insights into adverse molecular and cellular inflammatory responses induced by inhaled e-cig vapor in adolescents, a population targeted by e-cig companies and at risk for developing nicotine addiction and lifelong use of these devices.
“Genome organization in primate brain development.” Brain structure and development across primates, including humans and rhesus monkeys, is well conserved. The goal of this project is to better understand how and when genes (which encode proteins) are turned on during development by investigating the physical organization of DNA within neurons. Identifying genomic contributors to brain development will provide a means to hone in on potential mutations that contribute to neurodevelopmental disorders, such as autism.
“Non-invasive delivery of DNA-binding domains via stem cells in the nonhuman primate.” The field of genome engineering has undergone explosive growth in recent years. Delivery of gene regulators to target cells remains a significant challenge. The approach for this project utilizes mesenchymal stem/stromal cells (MSC), which have a strong safety profile, have the ability to modulate the immune system and create favorable microenvironments, and have been shown to serve as living biofactories to produce therapeutic proteins. This study will focus on the potential to accelerate the use of gene modifying and editing tools for disease modification and correction through the creation of a viable and efficient delivery platform using MSC and new gene editing approaches in the translational nonhuman primate model system.
2017-2018 Pilot Research Program Recipients
“Head-mounted imaging of cellular resolution calcium dynamics during neuroprosthetic learning.” Brain-machine interfaces (BMIs) offer enormous promise as a restorative therapy for patients with limb loss or immobility. Critically, they also offer a powerful tool for probing network modifications during sensorimotor learning, and recent studies have suggested that optimal engagement of learning is essential for robust neuroprosthetic control. The goal of this project is to move beyond the limited spatial resolution of current electrode-based BMIs to a cellular-resolution, optical-based BMI enabling investigation of clinically-relevant learning-related microcircuit plasticity. To do so, we will first develop a robust platform for calcium imaging in NHP by adapting and extending a commercially-available, miniature, one-photon fluorescence microscope, and then use this new platform to perform deep, cellular resolution, longitudinal calcium imaging of large numbers of neurons across layers of primary motor cortex in macaques during neuroprosthetic learning.
“Proof of concept of in vivo efficacy of existing drugs against Zika virus.” The Zika virus (ZIKV) is an emergent public health threat; a neglected tropical disease transformed into a pathogenic mosquito-borne and sexually transmitted human zoonosis. ZIKV is now linked to neurologic damage of both fetus and newborns, to systemic disease in adults and elderly, and to possible reproductive health and fertility complications. This pilot project builds on the non-human primate model for ZIKV infection previously developed at the CNPRC under a pilot project directed by Dr. Lark Coffey, and will test the antiviral activity of Nitazoxanide (a re-purposed existing licensed drug) for prevention and treatment of ZIKV infection and disease.
“Restoration of ovarian endocrine function and puberty in adolescent nonhuman primates with premature ovarian insufficiency.” Premature ovarian insufficiency (POI) is a common complication of anticancer treatments, such as chemotherapy and bone marrow transplantation, due to treatment toxicity. In female cancer survivors POI causes sterility, and loss of the ovarian endocrine function, which in turn results in premature osteopenia, muscle wasting, and accelerated cardiovascular disease. These long lasting effects are significant, particularly for young girls reaching puberty. In this pilot study we will investigate the capability of encapsulated allogeneic ovarian tissue to initiate physiological puberty in adolescent non-human primates, and the longevity of graft function along with the dynamics of the recipient’s immune response to a single and repeat transplantation. If successful, this approach will offer a clinically relevant and unexplored tool to restore ovarian endocrine function in young women with POI.
“Generation of mucosal adaptive immune responses with the novel, host-derived immunostimulant EP67.” Human cytomegalovirus (HCMV) infection is the primary cause of birth defects in the U.S. as well as morbidity and mortality in immunosuppressed transplant recipients. Systemic vaccines that generate long-lived protective immune responses throughout the body have failed to prevent HCMV infection in clinical trials despite 40+ years of research. Mucosal vaccines that additionally generate long-lived protective immune responses at the initial site of infection may prevent HCMV infection but are limited by the absence of potentially safe and effective mucosal adjuvants. We recently found that our novel host-derived immunostimulant, EP67, can act as a mucosal adjuvant in a mouse model of CMV. The current study will determine whether EP67 can act as a mucosal adjuvant in the more immunologically-relevant rhesus macaque model of CMV. This will have a positive impact on HCMV infection by providing a safe and effective mucosal adjuvant to identify mucosal vaccines against HCMV that are the most likely to protect the diverse human population. This work will also provide a strong platform for developing EP67-based mucosal vaccines against other pathogens that initially infect through mucosal surfaces and currently lack a licensed vaccine.
“Suprachoroidal delivery of viral vectors in nonhuman primate models of age-related macular degeneration (AMD).”Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly, but development of new therapies has been hindered by the lack of pre-clinical animal models. Most laboratory animals such as rodents are poor models of AMD because the macula is a specialized portion of the retina that has mainly evolved in primates to provide high-resolution central vision. The goals of our study are to employ state-of-the-art ocular imaging technologies to monitor AMD lesions that develop in geriatric rhesus macaques, and to evaluate a novel delivery system to deliver viral particles through the eye wall as a means for potential gene therapy.
2016-2017 Pilot Research Program Recipients
“Reversing progestin-mediated loss of the genital mucosal barrier with estrogen.” Our lab recently found that the injectable hormonal contraceptive depot-medroxyprogesterone acetate (DMPA) enhances mouse susceptibility to intravaginal HSV-2 infection by increasing genital mucosal permeability. On the other hand, treating mice with DMPA and estrogen protected mice from infection by improving mucosal barrier protection. Such work may offer the basis for an approach to hormonal contraceptive in which use of progestin and estrogen averts diminution of barrier protection created by progestin use alone. To extend our findings beyond the mouse, this pilot study will compare genital mucosal permeability in rhesus macaques (RM) treated systemically with DMPA or DMPA and estrogen. If similar effects are seen in the RM, we would explore use of estrogen-releasing vaginal rings in RM viral transmission studies and clinical investigation.
“Understanding Type-2 low asthma and peripheral airway disease through the study of stress-associated asthma in rhesus macaques.” Type-2 inflammation, or inflammation driven by the cytokines IL-4, -5 and -13 is clearly important in asthma and the UCSF Airway Clinical Research Center has developed methods to quantify T2 inflammation in the human airway. This work led to the concept of “T2 high” and “T2 low” asthma, which explains a large amount of heterogeneity in asthma severity and responsiveness to asthma treatments. However, current asthma animal models exclusively represent T2 high asthma. This has limited research into the biologic mechanisms that drive T2 low asthma and hampered development of treatment options for patients with T2 low disease. In this application we will test a novel T2 low animal model of asthma. Specially we will establish whether airway dysfunction in the setting of behavioral stress is characterized by low T2 inflammation, and perform a detailed airway characterization of macaques with stress associated asthma to determine how behavior stress leads to airway dysfunction.
“A closed-loop neural interface to enhance movements after stroke.” Stroke is the leading cause of disability in the United States, affecting over 700,000 patients each year. It is critical to develop novel technologies to promote motor rehabilitation. The goal of this project is to develop a systems neuroscience and computational model of the recovery process; a closely related goal is to test a neural engineering translational framework to improve motor function. These studies will lay the foundation for the development of neural interfaces to improve motor function and to reduce disability.
“A novel sustained ocular drug delivery system.” Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is a very promising treatment for the wet form of age-related macular degeneration, diabetic retinopathy and occlusive diseases. In fact, the number of intravitreal injections performed for AMD treatment in the Medicare population in US rose from 4,500 injections in 2001 to more than 2.3 million in 2012. It is estimated that this number is as high as 4.1 million when all indications for anti-VEGF use are included. While the therapeutic effects are positive, a major drawback is that this treatment must be repeated every four to six weeks for duration. The burden of monthly visits and frequent injections on patients, physicians and the health-care system cannot be ignored. Recently we have demonstrated that biodegradable microspheres and thermo-responsive hydrogel can be used as an ocular drug delivery system for anti-VEGF agents. The goal of this proposal is to demonstrate the same safety and efficacy in a nonhuman primate model that can facilitate introducing this technology into human clinical trials. We believe that our system will provide a practical and effective method to deliver anti-VEGF agents, and have a significant impact on the current healthcare system by reducing the frequency of injections and providing benefits of sustained treatment.
“Development of a nonhuman primate model of zika virus infection.” The availability of a primate model of Zika virus infection would be useful for understanding human Zika virus infection dynamics and disease. This pilot study is aimed at demonstrating proof-of-concept of Zika virus infection of macaques with potential effects on fetal development. This animal model will become a highly valuable resource to investigate the various aspects of pathogenesis and to test intervention strategies, including vaccines or other therapeutics, as well as strategies to interrupt transfusion or organ transmission to protect the human organ and blood supply. Such studies can guide clinical trials with the ultimate goal of curtailing the Zika virus pandemic.
2015-2016 Pilot Research Program Recipients
“Establishing a method for repeated intracerebral infusions of Aβ oligomers in rhesus monkeys.” Alzheimer’s disease is believed to be caused by the toxic actions on brain cells of a specific form of the beta-amyloid (A-beta) protein, the ‘oligomeric’ form. A-beta oligomers can cause changes in brain cells that resemble those seen in Alzheimer’s disease, when given to monkeys but not to rodents. Our pilot study will help us understand this phenomenon, particularly whether less frequent administration of A-beta oligomers still causes damage to brain cells. This will form the foundation of a study of whether the female sex hormone estradiol can protect brain cells in the living, intact primate brain from the Alzheimer’s-like damage caused by A-beta oligomers, directly testing the hypothesis that a specific hormone treatment in postmenopausal women may have a protective effect against developing Alzheimer’s disease.
“Intestinal commensal bacteria direct host resistance to pneumonia in neonates.” Human neonates are often treated with empiric antibiotics within the first week of birth. This interrupts the colonization of the neonatal intestine by commensal bacteria and is paradoxically associated with increased mortality for the neonate in form of pneumonia. This added an estimated $1.4 billion annually to the cost of treating preterm infants. Our long-term goal is to understand how excess antibiotic use contributes to increased risk of pneumonia. Our overall hypothesis is that intestinal commensal bacteria direct the development and functional maturation of innate immune cells. The proposed studies will establish a non-human primate model of neonatal pneumonia. We will test if commensal intestinal bacteria direct the accumulation of phenotypically and functionally distinct innate immune cells in the lungs and interrogate the functional significance of intestinal commensal bacteria in maintaining lung homeostasis. These studies will complement our results from neonatal mice and preterm humans. This will further our understanding of how intestinal colonization by commensal bacteria is a requisite for appropriate immune response in neonates.
“Comprehensive gene expression profiling of the developing macula in nonhuman primates: understanding cone photoreceptor differentiation”
“lnterruption of HIV-1 sexual transmission by small-molecule CD4-mimetic compounds.” Preventing sexual transmission of human immunodeficiency virus (HIV-1) is essential for stopping the global epidemic of acquired immunodeficiency syndrome (AIDS). We have discovered chemical compounds that block the entry of HIV-1 into cells and inactivate the virus. We will test whether these compounds can protect female monkeys from a simulated sexual exposure to an HIV-1-like virus. If successful, these studies could lead to approaches that prevent HIV-1 sexual transmission in humans.
2014-2015 Pilot Research Program Recipients
“The fate of inhaled statins in the lung and systemic circulation” The ultimate goal of this study is to develop novel inhaler therapies for lung diseases such as asthma, chronic bronchitis, and emphysema. We aim to use the ‘statins’, which are widely used drugs for the treatment of cardiovascular diseases, to reduce airway inflammation and scarring. Our initial pilot studies using a nonhuman primate model will test drug deposition in the lung and its metabolism, effect on lung immune cell populations, and the safety of inhaled simvastatin and pravastatin, two commonly used oral drugs in humans. If successful, this work may establish a new class of inhaler therapy for the treatment of chronic airway diseases in humans.
“A rhesus macaque immunogenicity model to investigate the effect of binding of complement factor H on meningococcal factor H binding protein vaccines” Vaccines for prevention of sepsis and meningitis caused by meningococci are available against serogroup A, C, W and Y but not B strains. Investigators at Children’s Hospital Oakland Research Institute (CHORI) and CNPRC are conducting a pilot study in nonhuman primates to determine the effect of binding of a host protein (complement Factor H) to a vaccine antigen known as Factor H binding protein (FHbp). This antigen is a component of two serogroup B vaccines being developed in the U.S.; one of these vaccines (Bexsero®, Novartis) recently was provided to two Universities in the U.S. for control of meningococcal outbreaks. This study is expected to provide valuable information for development of improved FHbp vaccines for humans with increased safety and efficacy against meningococcal disease.
“Potential new model for childhood gastroenteritis” Astroviruses are major causes of diarrhea worldwide, especially in the young, elderly, and immunocompromised. Yet, we have no “cure” for these constantly changing viruses. Once of the biggest hurdles to developing new therapies has been the lack of animal models that support human astrovirus infection. Through our pilot project, we hope to develop the first animal model to study this important cause of childhood gastroenteritis.
2013-2014 Pilot Research Program Recipients
“Role of oxytocin signaling in the amelioration of diet-induced obesity in nonhuman primates” The recent surge in the obesity epidemic is attributed, in part, to increased intake of high fructose corn syrup. Existing weight loss strategies are woefully ineffective and there is an urgent need for improved treatments for these diseases. While oxytocin is well known for its effects on reproductive behavior, it has gained recent attention for its therapeutic potential in the treatment of obesity in diet-induced obese (DIO) rodents. The overarching goal of this California National Primate Research Center Pilot Program project is to translate these findings from the laboratory to pre-clinical studies, and to test the hypothesis that chronic administration of oxytocin is a potential therapy that can reduce food intake and body weight in DIO nonhuman primates maintained on a high fructose diet. The data gained from this study will be critical to launch future work examining the mechanism by which oxytocin suppresses body weight and its efficacy for long-term weight management.
“Determination of age-related effects on mesenchymal stem/stromal cell (MSC) function on hematopoietic stem cell (HSC) engraftment and B cell regeneration in the rhesus monkey, Macaca mulatta” Mesenchymal stromal cells (MSCs) are cells in the bone marrow that serve dual functions: they are precursors of mature bone and they also support hematopoietic stem cells (HSCs) from which all blood cell types are derived. In recent years, MSCs have been proposed to regulate immune responses as well as facilitate the engraftment of HSCs after transplantation in the bone marrow. Our proposed studies aim to understand the mechanisms that control cellular “crosstalk” between MSCs and HSCs. Using a clinically relevant nonhuman primate model, we will investigate age-related changes in MSCs and whether these changes affect HSC behavior, including the potential effects of nonmyeloablative conditioning typically used prior to HSC transplantation on MSC function.
“Lung regeneration following partial pneumonectomy in macaques” Lung diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis, are a major cause of sickness and death. There are very few treatment options for patients with advanced lung disease. We hope to identify stem cells in the adult lung that have the ability to repair damaged lung tissue. A deeper understanding of these cells has the potential to lead to new cellular and molecular therapies for lung disease.