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.

项目摘要/摘要 这项针对K08指导的临床科学家职业发展奖的四年提案旨在促进 候选人的专业技能丹尼尔·E·迈达娜（Daniel E. Maidana），医学博士，博士 与一单核吞噬细胞对残留脱离的光感受器（PR）细胞死亡的贡献有关 （RD）。候选人的职业和科学目标依赖于所需的受保护的研究时间 高级实验室方法并在专家的指导下发展领导技能 多学科指导团队。这项协作工作以先验研究为基础，并建立了 指导关系将为成功和产品过渡到独立性提供基础。 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大学（UIC）将包括I）免疫学，生物统计学，生物统计学的研究生课程 在UIC上，转录组学和生物信息学； ii）高级实验室技术和分析方法，以 专家指导和咨询委员会； iii）发展管理和心理技能的发展 领导一个富有成效的独立实验室。机构环境，部门支持和交叉 纪律指导团队将使候选人在这四年中最大程度地提高生产力。这 UIC的眼科和视觉科学系在早期过渡方面有一致的记录 身体科学家们建立了独立研究人员，并强烈支持该奖项的候选人。 该提案的科学目标是定义残留小胶质细胞（MG）和血液的独立贡献 在RD实验模型中，衍生的单核细胞/巨噬细胞（Mø），以降临和视力丧失。自毫克以来 Mø可以有助于或解决最初的伤害，最近已经采用了几种治疗方法 提议调节这些细胞。但是，最近的工作已经揭示了技术限制，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角色的理解 在促进或减少PR细胞死亡方面。这个目标将使用新颖的有条件实现 删除模型i）定义MG在早期死亡PR清除中的作用； ii）剖析MG的贡献 和Mø表型在后期促进公关的灭亡； iii）确定MG的神经保护潜力 并在RD之后挽救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Mø的理解方面的科学进步。我们希望这项工作能够提供机械 开发有效的神经保护疗法的见解，使我们能够最大程度地提高分离的视觉效果 视网膜以防止视力丧失。