Neuroprotective Mechanisms of Inosine Monophosphate Dehydrogenase Inhibitors in Retinitis Pigmentosa

 描述（由申请人提供）：这是一个为期五年的辅导职业发展培训计划的建议，保罗杨，医学博士，博士，在凯西眼科研究所（CEI）在俄勒冈州健康与科学大学（OHSU）。杨博士是中国环境研究院新任命的助理教授，他负责治疗遗传或免疫介导的视网膜变性患者。作为一名临床科学家，他的目标是更好地了解这些疾病，为患者带来新的治疗方法。虽然杨博士拥有神经生理学背景以及在眼部免疫学和眼科遗传学方面的丰富临床经验，但此时的K08奖对于支持他掌握将新治疗从实验室带到床边所需的知识和技能所需的指导和博士后培训至关重要。 OHSU是美国国立卫生研究院资助的主要机构之一，致力于为支持和发展杨博士等临床科学家提供丰富的学术环境。作为对医生科学家指导的承诺的反映，在过去的5年里，CEI有三位K08职业发展奖的获得者。CEI不仅是一个卓越的临床中心，也是诊断和治疗视网膜变性的前沿转化研究发展的领导者。转化临床试验中心（TCTC）是CEI的一个独特方面，它有能力促进新疗法的发展，例如本研究中提出的那些， 临床前评价转化为临床试验。拟议的培训计划是由一个转化研究组成部分和涉及TCTC的临床组成部分。 OHSU的两位杰出科学家在使用技术研究小动物模型中的视网膜变性方面具有互补的专业知识，他们是Catherine Morgans博士和Robert Duvoisin博士，他们将担任Yang博士的研究导师。同时，医学博士Richard Weleber将担任Yang博士的临床导师。Weleber博士拥有超过35年的遗传性视网膜变性研究经验，作为TCTC的创始成员，他将为遗传性视网膜变性临床试验的开发和实施提供临床前数据评估方面的临床培训和指导。杨博士将成为TCTC的指导成员。Morgans博士、Duvoisin博士和Weleber博士完美地结合在一起，为杨博士提供了实现目标所需的广泛的实践和智力培训， 拟议的研究和职业发展培训计划的目标。 拟议的研究将开发新的疗法来减缓或停止视网膜色素变性（RP）的视网膜变性，这将对公共卫生产生潜在的重大影响，因为RP是年轻人不可治愈的失明的最常见遗传原因。虽然RP是一种异质性遗传疾病，但有证据表明，感光细胞死亡的共同途径是由环磷酸鸟苷（cGMP）水平高度升高引起的，而感光细胞毒性则由小胶质细胞活化和炎性细胞因子表达加剧。霉酚酸酯（MMF）和其他肌苷一磷酸脱氢酶（IMPDH）抑制剂可通过降低cGMP的鸟苷酸前体水平以及抑制小胶质细胞活化来减缓光感受器变性。事实上，初步数据表明，MMF确实能够在rd10小鼠中产生强大的神经保护作用，rd10小鼠是RP的原型模型。拟议研究的目的是表征IMPDH抑制剂在rd10小鼠中的作用，确定IMPDH抑制剂是否可以调节rd10小鼠和视网膜培养物中的鸟苷酸池和感光细胞死亡，并确定IMPDH抑制剂是否可以抑制rd10小鼠中小胶质细胞活化和炎性细胞因子的表达。为了实现这些具体目标，杨博士将需要K08奖的支持，以获得小动物技术，视网膜免疫组织化学，视网膜外植体培养，视网膜全载片，全视网膜ELISA和全视网膜定量逆转录酶PCR的新技能，以及对核苷酸的整个视网膜水平和利用高浓度的药物进行定量，高效液相色谱和液相色谱串联质谱。 K08奖在这个时候将产生最大的影响，不仅支持一组无法治愈的致盲疾病的新治疗策略的创新研究，而且还大大促进了杨博士的职业发展，成为一名独立的NIH资助的研究人员，能够进行新治疗的临床前研究并通过临床试验。

 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.