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

项目总结 NIH导师研究职业发展奖申请的目标是促进 候选人成为一名独立的临床医生兼科学家。她的长期职业目标是把她的技能用在 比较眼科学和分子遗传学开发治疗人类失明的新疗法 由干性形式的老年性黄斑变性(AMD)引起的，目前有一种治疗方法没有得到满足 需要。她在这个为期4年的K08项目中的短期目标是培训毒物诱导的病理机制 以及在动物模型中模拟人类暴露。她将利用和的独特环境。 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 她的实验室离杜克大学和国家环境研究所很近 健康科学，导师和合作者所在的地方。职业发展计划的主要内容 包括来自一个不同指导委员会的支持，该委员会具有与提案所有方面有关的专门知识， 横跨AMD的毒理学、线粒体生物学、视网膜电图学和动物模型。候选人将会 参加毒理学、电子显微镜和视网膜电描记术的教学培训，出席会议， 发表她的工作，并最终向国家眼科研究所(NEI)提交一份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。该项目 将确定香烟烟雾有毒物质对苯二酚暴露对线粒体的影响 黄斑光感受器和RPE的密度、形态和功能，并将定义不同的作用(S) 线粒体上过氧化物酶体增殖物激活受体γ共激活物1-α(Pgc1α)的亚型 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前列环素α活性。这个 具体目标是：1：确定对苯二酚暴露是否损害黄斑光感受器功能 并在相关动物模型中降低前列环素α和线粒体密度。2：确定是否删除 特定的前列环素α亚型导致小鼠AMD样疾病的发生以及这是否可以 因对苯二酚而加重。 这项工作有望为为什么黄斑最容易患干性AMD提供重要的见解。这个 黄斑易感性的机制还不清楚，因此这项研究与 NEI。这项工作还将导致发现视网膜线粒体健康的新媒介，这可能是 治疗干性AMD的候选药物。

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.