Responses of the Macula to Toxicant Injury: The Role(s) of PGC1α Isoforms in Photoreceptor Neuroprotection

项目摘要 这个NIH指导研究职业发展奖申请的目标是促进过渡， 成为一名独立的临床科学家。她的长期职业目标是将她的技能应用于 比较眼科学和分子遗传学开发新的治疗方法，以解决人类失明 老年性黄斑变性（AMD）是由老年性黄斑变性（AMD）的干性形式引起的， 需要的她在这个为期4年的K08计划的短期目标是在毒物诱导的病理机制的培训 并在动物模型中模拟人类暴露。她将利用独特的环境， 北卡罗来纳州州立大学周围，包括北卡罗来纳州P30资助的人类健康和环境中心 她的实验室靠近杜克大学和国家环境研究所 健康科学，导师和合作者所在的地方。职业发展计划的关键要素 包括一个多元化的指导委员会的支持，该委员会具有与提案的各个方面相关的专业知识， 涵盖毒理学、线粒体生物学、视网膜电图和AMD动物模型。候选人将 参加毒理学、电子显微镜和视网膜电图方面的教学培训，出席会议， 发表她的工作，并最终向国家眼科研究所（NEI）提交R01提案。 候选人的研究项目与她的职业目标和培训计划完美结合。项目 将确定暴露于香烟烟雾毒物对苯二酚对线粒体的影响， 本发明涉及黄斑光感受器和RPE中的密度、形态和功能，并且将定义不同光感受器和RPE的作用。 线粒体过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC1 α）亚型 视网膜的健康 将使用新的动物模型来研究黄斑光感受器和PGC1 α活性。的 具体目的是：1：确定氢醌暴露是否损害黄斑感光功能 并在相关动物模型中降低PGC1 α和线粒体密度。2：确定是否删除 特异性Pgc1 α亚型导致小鼠AMD样疾病的发生， 对苯二酚加剧了病情 这项工作预计将产生重要的见解，为什么黄斑遭受最干燥的AMD。的 黄斑易感性的机制定义不清，因此该研究与以下使命相关： 的NEI。这项工作还将导致发现视网膜线粒体健康的新介质，这可能是 作为干性AMD治疗的候选物。

PROJECT SUMMARY The goal of this NIH Mentored Research Career Development Award application is to facilitate the transition of the candidate into an independent clinician-scientist. Her long-term career goal is to apply her skills in comparative ophthalmology and molecular genetics to develop novel treatments to address human blindness caused by the dry form of age-related macular degeneration (AMD), for which there is an unmet therapeutic need. Her short-term goal in this 4-year K08 program is to train in mechanisms of toxicant-induced pathology and modelling human exposures in animal models. She will capitalize on the unique environment in and around NC State University, including the NC State P30 funded Center for Human Health and the Environment and the close proximity of her laboratory to both Duke University and the National Institute for Environmental Health Sciences, where mentors and collaborators are located. Key elements of the career development plan include support from a diverse mentorship committee with expertise relating to all aspects of the proposal, spanning toxicology, mitochondrial biology, electroretinography and animal models of AMD. The candidate will participate in didactic training in toxicology, electron microscopy and electroretinography, present at meetings, publish her work, and ultimately, submit an R01 proposal to the National Eye Institute (NEI). The candidate’s research project integrates optimally with her career goals and training program. The project will determine the consequences of exposure of the cigarette smoke toxicant hydroquinone on mitochondrial density, morphology and function in macular photoreceptors and RPE, and will define the role(s) of different isoforms of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) on mitochondrial health in the retina. Novel animal models will be used that enable study of macular photoreceptors and PGC1α activity. The specific aims are: 1: To determine whether hydroquinone exposure impairs macular photoreceptor function and reduces PGC1α and mitochondrial density in a relevant animal model. 2: To determine whether deletion of specific Pgc1α isoforms leads to development of AMD – like disease in mice and whether this can be exacerbated by hydroquinone. This work is expected to yield important insights into why the macula suffers most from dry AMD. The mechanisms of macular susceptibility are poorly defined, and the study is therefore relevant to the mission of the NEI. The work will also lead to discovery of novel mediators of retinal mitochondrial health, which may be candidates as treatments for dry AMD.