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

定义视网膜小胶质细胞和浸润单核细胞对视网膜脱离感光细胞死亡的作用

• 批准号: 10644354
• 负责人: Daniel Enrique Maidana
• 金额: $ 21.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644354
• 关键词: Ablation; Acute; Address; Adult; Advisory Committees; Affect; Age; Award; Bioinformatics; Biological Assay; Biometry; Blindness; Blood; Bone Marrow; Career Mobility; Cell Death; Cells; Chicago; Chimera organism; Chronic; Clinical; Data; Death Rate; Development; Doctor of Philosophy; Early treatment; Emergency Situation; Environment; Experimental Models; Goals; Illinois; Immunology; Immunophenotyping; Impairment; Infiltration; Inflammatory; Inflammatory Response; Injury; Institution; K-Series Research Career Programs; Kinetics; Laboratories; Leadership; Macrophage; Macrophage Colony-Stimulating Factor Receptor; Maps; Mediating; Mentors; Mentorship; Methods; Microglia; Modeling; Mononuclear; Morphology; Mus; Myeloid Cells; Necrosis; Newborn Infant; Ophthalmology; Outcome; Patients; Peripheral; Phagocytes; Phase; Phenotype; Photoreceptors; Physicians; Productivity; Publishing; Reporter; Research; Research Personnel; Retina; Retinal Detachment; Retinal Diseases; Role; Scientific Advances and Accomplishments; Scientific Inquiry; Scientist; Specificity; System; Target Populations; Therapeutic; Time; Tyrosine Kinase Inhibitor; Universities; Visual; Woman; Work; analytical method; career; clinically relevant; demographics; ethnic minority; experimental study; inherited retinal degeneration; inhibitor; insight; monocyte; multidisciplinary; neuroprotection; novel; photoreceptor degeneration; prevent; professor; racial minority; repaired; response; skills; small molecule; transcriptome; transcriptomics; translational approach; translational potential; vision science

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.

项目概要/摘要 这项为期四年的 K08 指导临床科学家职业发展奖提案旨在进一步推动 候选人 Daniel E. Maidana（医学博士、哲学博士）在解决关键科学问题时的专业技能 与单核吞噬细胞对视网膜脱离中光感受器（PR）细胞死亡的贡献有关 (RD) 候选人提出的职业和科学目标取决于受保护的必要研究时间。 在专家的指导下掌握先进的实验室方法并培养领导能力 这项协作工作建立在先前的研究基础上。 指导关系将为成功、富有成效地向独立过渡提供基础。 目前担任眼科助理教授的候选人的职业发展计划 伊利诺伊大学芝加哥分校 (UIC) 将包括 i) 免疫学、生物统计学、 UIC 的转录组学和生物信息学； ii) 先进的实验室技术和分析方法，以 专家指导和咨询委员会； iii) 发展所需的管理和指导技能 领导一个富有成效的、独立的实验室。 纪律指导团队将使候选人在这四年中最大限度地提高生产力。 UIC眼科和视觉科学系在早期过渡方面有着一贯的记录 医生科学家建立了独立的研究人员，并强烈支持该奖项的候选人。 该提案的科学目标是定义视网膜小胶质细胞（MG）和血液的独立贡献 自 MG 以来，衍生性单核细胞/巨噬细胞 (Mø) 导致 PR 死亡和视力丧失的实验模型。 和 Mø 可以促进或解决最初的损伤，最近出现了几种治疗方法 然而，最近的工作揭示了技术的局限性和缺乏。 用于消融 MG 和 Mø 的方法的特异性，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通过使用新型诱导条件条件来实现。 删除模型 i) 定义 MG 在早期 RD 死亡 PR 清除中的作用；ii) 剖析 MG 的贡献 和 Mø 表型促进晚期 RD 中的 PR 消亡；以及 iii) 确定 MG 的神经保护潜力 和 Mø 来挽救 RD 后的 PR 细胞死亡。该提案的成功完成将产生技术成果。 以及我们对 MG 和 Mø 的理解的科学进步，我们希望这项工作能够提供机制。 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独立患者的视觉效果 视网膜以防止视力丧失。