Neuroprotective Mechanisms of Inosine Monophosphate Dehydrogenase Inhibitors in Retinitis Pigmentosa

肌苷单磷酸脱氢酶抑制剂对色素性视网膜炎的神经保护机制

• 批准号: 9088902
• 负责人: Paul Yang
• 金额: $ 21.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088902
• 关键词: Adverse drug effect; Adverse effects; Animal Model; Animals; Appearance; Award; Blindness; Cell Count; Cell Death; Clinical; Clinical Trials; Conduct Clinical Trials; Cyclic GMP; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Dose; Environment; Enzyme-Linked Immunosorbent Assay; Etiology; Eye; FDA approved; Foundations; Funding; Genetic; Genetic Transcription; Goals; Guanine; Guanosine; Health Sciences; Hereditary Disease; High Pressure Liquid Chromatography; Immune; Immunohistochemistry; Immunology; Inflammation; Inflammatory; Inherited; Inosine Monophosphate; Inosine Monophosphate Dehydrogenase Inhibitor; Institutes; Institution; K-Series Research Career Programs; Knowledge; Liquid Chromatography; Mediating; Mentors; Mentorship; Microglia; Microscopy; Modeling; Mus; Mycophenolate; Nucleotides; Oral; Oregon; Organ Transplantation; Oxidoreductase; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Photoreceptors; Physicians; Physiology; Plasma; Prevalence; Public Health; Quantitative Reverse Transcriptase PCR; Reflex action; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinitis Pigmentosa; Reverse Transcription; Rheumatology; Rodent Model; Route; Scientist; Specificity; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Training; Training Programs; Translational Research; Translations; Treatment Efficacy; United States National Institutes of Health; Universities; Yang; bench to bedside; career development; cytokine; cytotoxicity; experience; immunoreactivity; in vitro Assay; inherited retinal degeneration; innovation; intraperitoneal; member; migration; mycophenolate mofetil; neurophysiology; neuroprotection; nonhuman primate; novel; novel therapeutics; photoreceptor degeneration; post-doctoral training; pre-clinical research; preclinical evaluation; preclinical study; professor; public health relevance; research and development; skills; tandem mass spectrometry; translational clinical trial; treatment strategy; young adult

 DESCRIPTION (provided by applicant): This is a proposal for a five-year mentored career development training program for Paul Yang, MD, PhD, at the Casey Eye Institute (CEI) at Oregon Health & Science University (OHSU). Dr. Yang is a newly- appointed assistant professor at CEI, who cares for patients with retinal degeneration from genetic or immune- mediated etiology. His goal as a clinician scientist is to better understand these diseases in an effort to bring novel treatments to patients. While Dr. Yang has a background in neurophysiology and strong clinical experience in ocular immunology and ophthalmic genetics, a K08 award at this time would be crucial to supporting the mentorship and postdoctoral training necessary for him to master the knowledge and skills required for bringing a novel treatment from bench to bedside. OHSU is one of the premier NIH-funded institutions committed to providing a rich academic environment for the support and development of clinician scientists, such as Dr. Yang. As a reflection of this commitment to the mentorship of physician scientists, there have been three recipients of the K08 career development award within the last 5 years at the CEI. The CEI is not only a center of clinical excellence, but also a leader in the development of cutting-edge translational research for the diagnosis and treatment of retinal degeneration. The Translational Clinical Trials Center (TCTC) is a unique aspect of the CEI that would have the capacity to facilitate the path of novel treatments, such as those proposed in this study, from preclinical evaluation into clinical trials. The proposed training program is composed of a translational research component and a clinical component involving the TCTC. The two eminent scientists at OHSU with complementary expertise in the use of techniques to study retinal degeneration in small animal models are Catherine Morgans, PhD and Robert Duvoisin, PhD, who will serve as research mentors to Dr. Yang. Concurrently, Richard Weleber, MD will serve as clinical mentor to Dr. Yang. With over thirty-five years of experience studying inherited retinal degeneration and as a founding member of the TCTC, Dr. Weleber will provide clinical training and guidance in the evaluation of preclinical data to the development and conduct of clinical trials for inherited retinal degeneration. Dr. Yang will be a mentored-member of the TCTC. Together, Drs. Morgans, Duvoisin, and Weleber are perfectly matched to provide Dr. Yang with the breadth of practical and intellectual training required to achieve the objectives and goals of the proposed research and career development training program. The proposed research will be to develop novel therapies to slow or halt retinal degeneration in retinitis pigmentosa (RP), which will have a potentially significant impact on public health as RP is the most commonly inherited cause of untreatable blindness in young adults. While RP is a heterogeneous genetic disorder, there is evidence of a common pathway of photoreceptor cell death that is induced by highly-elevated levels of cyclic guanosine monophosphate (cGMP), and photoreceptor cytotoxicity that is exacerbated by microglia activation and expression of inflammatory cytokines. Mycophenolate mofetil (MMF) and other inosine monophosphate dehydrogenase (IMPDH) inhibitors may slow photoreceptor degeneration by mitigating the levels of guanosine nucleotide precursors to cGMP, as well as suppressing microglia activation. Indeed, preliminary data show that MMF is indeed capable of a robust neuroprotective effect in rd10 mice, which is a prototypical model of RP. The aims of the proposed research are to characterize the effect of IMPDH inhibitors in rd10 mice, determine whether IMPDH inhibitors can modulate guanosine nucleotide pools and photoreceptor cell death in rd10 mice and retinal cultures, and determine whether IMPDH inhibitors can inhibit microglia activation and expression of inflammatory cytokines in rd10 mice. To accomplish these specific aims, Dr. Yang will need the support of a K08 award to obtain new skills in small animal techniques, retinal immunohistochemistry, retinal explant cultures, retinal whole mounts, whole retina ELISA, and whole retina quantitative reverse transcriptase PCR, as well as quantification of whole retinal levels of nucleotides and medications utilizing high-performance liquid chromatography and liquid chromatography tandem mass spectrometry. A K08 award at this time would have maximal impact, not only supporting innovative research for a new treatment strategy for a group of incurable blinding diseases, but also significantly advancing Dr. Yang's career development to become an independent NIH-funded investigator capable of carrying out the preclinical research of a novel therapeutic and taking it through clinical trials.