Defining the Role of Retinal Microglia and Infiltrating Monocytes on Photoreceptor Cell Death in Retinal Detachment

项目总结/摘要 这项为期四年的K 08指导临床科学家职业发展奖提案旨在进一步推动 候选人的专业技能丹尼尔E. Maidana，医学博士，博士，同时解决关键的科学问题 视网膜脱离中单核吞噬细胞对感光细胞死亡的贡献 （RD）。候选人提出的职业和科学目标依赖于受保护的研究时间， 掌握先进的实验室方法，并在专家的指导下培养领导能力 多学科指导团队。这项合作工作建立在先前的研究基础上， 辅导关系将为成功和富有成效地过渡到独立奠定基础。 候选人的职业发展计划，目前是眼科助理教授， 伊利诺伊大学芝加哥分校（UIC），将包括i）免疫学，生物统计学， 转录组学和生物信息学，在UIC; ii）先进的实验室技术和分析方法，由 一个专家指导和咨询委员会; iii）发展管理和指导技能， 领导一个富有成效的独立实验室。机构环境、部门支持和跨部门合作 学科导师团队将使候选人在这四年中最大限度地提高生产力。的 UIC的眼科和视觉科学系在早期过渡方面有着一致的记录 医生科学家建立独立的调查人员，并大力支持这一奖项的候选人。 这项提案的科学目标是确定视网膜小胶质细胞（MG）和血液的独立贡献， 衍生的单核细胞/巨噬细胞（MCAH）在RD的实验模型中导致PR死亡和视力丧失。由于MG 和二尖瓣可以促进或解决初始损伤，最近已经有几种治疗方法， 来调节这些细胞。然而，最近的工作揭示了技术上的局限性， 在用于消融MG和MMPs的方法中存在特异性，因此限制了我们对其独立作用的理解 促进或减少PR细胞死亡。这一目标将使用一种新的诱导条件 缺失模型，以i）定义MG在早期RD中死亡PR清除中的作用; ii）分析MG的贡献 和MG表型促进晚期RD中PR死亡;和iii）确定MG的神经保护潜力 和MIBI以挽救RD后的PR细胞死亡。该提案的成功完成将产生技术 以及我们对MG和Møs了解的科学进步。我们希望这项工作能提供机械的 洞察力，以开发有效的神经保护疗法，使我们能够最大限度地提高视力的结果，在分离 视网膜，以防止视力下降。

Project Summary/Abstract This four-year proposal for the K08 Mentored Clinical Scientist Career Development Award aims to further the professional skills of the candidate Daniel E. Maidana, MD, PhD while addressing critical scientific inquiries related to the contribution of mononuclear phagocytes to photoreceptor (PR) cell death in retinal detachment (RD). The candidate's proposed career and scientific goals rely on the protected research time necessary to master advanced laboratory methods and develop leadership skills under the guidance of an expert multidisciplinary mentoring team. This collaborative work, which builds on prior research and established mentoring relationships, will provide the basis for a successful and productive transition to independence. The career advancement plan for the candidate, currently an Assistant Professor of Ophthalmology at the University of Illinois at Chicago (UIC), will consist of i) graduate-level courses in immunology, biostatistics, transcriptomics, and bioinformatics, at UIC; ii) advanced laboratory technical and analytical methods, guided by an expert Mentoring and Advisory Committee; iii) development of management and mentoring skills required to lead a productive, independent laboratory. The institutional environment, departmental support, and cross- disciplinary mentorship team will enable the candidate to maximize productivity during these four years. The Department of Ophthalmology and Visual Sciences at UIC has a consistent record in transitioning early physician-scientists to established independent investigators and strongly supports the candidate for this award. The scientific goal of this proposal is to define the independent contribution of retinal microglia (MG) and blood- derived monocytes/macrophages (Mø) to PR demise and vision loss in an experimental model of RD. Since MG and Mø can either contribute to or resolve the initial injury, several therapeutic approaches have been recently proposed to modulate these cells. However, recent work has unveiled technical limitations and a lack of specificity in the methods used to ablate MG and Mø, thus limiting our understanding of their independent role in promoting or reducing PR cell death. This goal will be accomplished using a novel inducible conditional deletion model to i) define the role of MG in dead PR clearance in early RD; ii) dissect the contribution of MG and Mø phenotypes to promote PR demise in late RD; and iii) determine the neuroprotective potential of MG and Mø to rescue PR cell death following RD. The successful completion of this proposal will generate technical and scientific advancements in our understanding of MG and Mø. We expect this work to provide mechanistic insights to develop effective neuroprotective therapies, allowing us to maximize visual outcomes in the detached retina to prevent vision loss.