Neuroprotective Mechanisms of Inosine Monophosphate Dehydrogenase Inhibitors in Retinitis Pigmentosa

 描述(由申请人提供)：这是俄勒冈健康与科学大学(OHSU)凯西眼科研究所(CEI)为Paul Yang医学博士提供的为期五年的指导式职业发展培训计划的建议书。杨博士是CEI新任命的助理教授，负责照顾因遗传或免疫介导的病因而导致的视网膜变性患者。作为一名临床科学家，他的目标是更好地了解这些疾病，努力为患者带来新的治疗方法。虽然杨博士在神经生理学方面有背景，在眼部免疫学和眼科遗传学方面也有丰富的临床经验，但此时获得K08奖将是支持导师和博士后培训的关键，因为他需要获得必要的指导和博士后培训，以掌握将一种新疗法从医生带到床边所需的知识和技能。OHSU是美国国立卫生研究院资助的一流机构之一，致力于为杨博士等临床科学家的支持和发展提供丰富的学术环境。作为对内科科学家导师的承诺的反映，在过去的5年里，CEI已经有三名K08职业发展奖的获奖者。CEI不仅是临床卓越的中心，而且在诊断和治疗视网膜变性的尖端翻译研究方面也处于领先地位。转化型临床试验中心(TCTC)是CEI的一个独特方面，它将有能力促进新疗法的发展，如本研究中提出的那些，从 进入临床试验的临床前评估。拟议的培训计划由翻译研究部分和涉及TCTC的临床部分组成。OHSU在使用技术研究小动物模型视网膜变性方面拥有互补专业知识的两位著名科学家是Catherine Mangers博士和Robert Duvoisin博士，他们将担任杨博士的研究导师。同时，理查德·韦勒伯医学博士将担任杨医生的临床导师。韦勒伯博士拥有超过35年的研究遗传性视网膜变性的经验，作为TCTC的创始成员之一，他将为遗传性视网膜变性临床试验的开发和进行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。摩根博士、杜沃辛博士和韦勒伯博士结合在一起，为杨博士提供了实现目标和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。这项拟议的研究将开发新的疗法来减缓或阻止视网膜色素变性(RP)，这将对公众健康产生潜在的重大影响，因为RP是年轻人无法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，光感受器细胞死亡的共同途径是由高水平的环鸟苷一磷酸(CGMP)诱导的，而光感受器细胞毒性则因小胶质细胞的激活和炎性细胞因子的表达而加剧。霉酚酸酯(MMF)和其他肌苷一磷酸脱氢酶(IMPDH)抑制剂可能通过减轻cGMP的鸟苷核苷酸前体水平以及抑制小胶质细胞的激活来减缓光感受器的退化。事实上，初步数据表明，MMF确实能够在rd10小鼠身上发挥强大的神经保护作用，这是RP的典型模型。本研究的目的是确定IMPDH抑制剂在RD10小鼠体内的作用，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核苷酸池和光感受器细胞死亡，并确定IMPDH抑制剂是否可以抑制RD10小鼠小胶质细胞的激活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奖项的支持，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、视网膜整体培养、全视网膜ELISA法和全视网膜定量逆转录酶聚合酶链式反应的新技能，以及利用高效液相色谱和高效液相串联质谱仪定量测定全视网膜的核苷酸和药物水平。此时授予K08奖项将产生最大的影响，不仅支持针对一组不可治愈的致盲疾病的新治疗策略的创新研究，还将极大地推动杨博士的职业发展，使其成为一名由NIH资助的独立研究人员，能够对一种新的治疗方法进行临床前研究并进行临床试验。

 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.