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

项目摘要/摘要 这项为期四年的K08临床科学家导师职业发展奖提案旨在进一步 候选人Daniel E.Maidana，医学博士，在解决关键科学问题时的专业技能 视网膜脱离中单核巨噬细胞对光感受器细胞死亡的影响 (D)。候选人提出的职业和科学目标依赖于必要的受保护的研究时间 掌握先进的实验室方法，在专家的指导下培养领导技能 多学科指导团队。这项协作工作建立在先前研究的基础上，并建立了 指导关系，将为成功和富有成效的独立过渡奠定基础。 候选人的职业发展计划，目前是该大学眼科学助理教授 伊利诺伊大学芝加哥分校(UIC)将包括1)免疫学、生物统计学、 转录学和生物信息学；二)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；三)发展管理和指导技能，以 领导一个高效、独立的实验室。制度环境、部门支持、跨部门 纪律指导团队将使应聘者在这四年中最大限度地提高生产率。这个 UIC的眼科和视觉科学系在早期过渡方面的记录始终如一 授予内科科学家和著名的独立研究人员，并大力支持这一奖项的候选人。 这项提议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/巨噬细胞(Mø)在RD实验模型中导致PR死亡和视力丧失。自MG以来 而莫尔可以促成或解决最初的损伤，最近已经有了几种治疗方法 建议对这些细胞进行调节。然而，最近的研究揭示了技术上的局限性和缺乏 用于消融MG和Mø的方法的特殊性，从而限制了我们对它们独立作用的理解 促进或减少PR细胞死亡。这一目标将使用一种新的可诱导条件来实现 缺失模型：1)确定MG在RD早期死亡PR清除中的作用；2)剖析MG的贡献 以及促进RD晚期PR死亡的表型；以及iii)决定MG的神经保护潜力 和摩尔挽救RD后PR细胞的死亡。该提案的成功完成将产生技术上的 以及我们对MG和Mø的理解方面的科学进步。我们希望这项工作能提供机械性 开发有效的神经保护疗法的见解，使我们能够最大限度地提高孤立者的视觉效果 防止视力丧失的视网膜。

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.