About the Pilot Research Program
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.
The 2016 Call for Pilot Project Letters of Intent can be downloaded here.
The 2016 Pilot Research Program as completed review of proposals and awardees have been notified.
Please contact the Associate Director of Research firstname.lastname@example.org if you would like to be added to the CNPRC Pilot Research Program list serve for notification of new funding opportunities.
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.