Transcriptional signatures of glaucomatous retinal and optic nerve head cells

青光眼视网膜和视神经乳头细胞的转录特征

基本信息

批准号：
10524883
负责人：
Aboozar Monavarfeshani
金额：
$ 11.86万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2023-07-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524883
关键词：
Advisory Committees Affect Age American Anatomy Animal Model Animals Area Astrocytes Autopsy Award Axon Biomechanics Blindness Boston Brain Candidate Disease Gene Cell Death Cell Nucleus Cell Survival Cells Cessation of life Cicatrix Ciliary Body Clinical Communication Computational Biology Connective Tissue Cornea Data Development Development Plans Eye Failure Freezing Frequencies Gene Expression Gene Expression Alteration Gene Expression Profile Genes Genetic Glaucoma Histologic Human Immunohistochemistry Impairment In Situ Hybridization Individual Injury Investigation Iris Light Longevity Mentors Methods Modeling Molecular Mus Natural regeneration Neuraxis Neurobiology Neuroglia Neurons Neuroprotective Agents Nuclear Optic Disk Optic Nerve Outcome Pathogenesis Patients Pediatric Hospitals Peripheral Persons Pharmaceutical Preparations Phase Physiologic Intraocular Pressure Predisposition Primary Open Angle Glaucoma Principal Investigator Process Protocols documentation RNA Race Regulator Genes Research Research Institute Research Personnel Research Training Retina Retinal Ganglion Cells Risk Factors Rodent Role Sampling Science Sclera Signal Transduction Site Small Nuclear RNA Structure of retinal pigment epithelium Supervision Therapeutic Time Tissues Trabecular meshwork structure Translating Universities Vision Western Blotting career development cell type clinical investigation conjunctiva differential expression effective therapy experience high intraocular pressure improved in vivo insight lens loss of function macula modifiable risk mouse model multidisciplinary neuroprotection novel preclinical study prevent programs retinal neuron sex therapeutic target transcriptome transcriptome sequencing visual information

项目摘要

Project Summary Glaucoma is one of the leading causes of irreversible blindness in the US and worldwide. The loss of retinal ganglion cells (RGCs) — neurons that convey visual information to the brain — is a hallmark of glaucoma. Elevated intraocular pressure (IOP) is a major risk factor for most types of glaucoma, and lowering it remains the only effective treatment for slowing vision loss. However, many patients with seemingly controlled IOP still experience progressive loss of vision, underscoring the unmet need for neuroprotective therapies that could keep RGCs alive, either alone or in combination with IOP-lowering drugs. A critical obstacle toward developing neuroprotective therapeutics is the lack of true mechanistic understanding of RGC death, neuroprotection, and survival. Animal models of glaucoma fail to capture some features of the human glaucoma, including the gradual progression of vision loss and remodeling of the connective tissues of optic nerve head (ONH). Thus, there is a critical need to directly investigate the mechanisms that underlie death of RGCs in human glaucoma. This proposal aims to uncover such molecular mechanisms though direct analysis of postmortem human retinas. The transcriptional profile of macular and peripheral RGCs, and all cells residing at the ONH will be obtained from genetically and clinically defined human donors (healthy controls and glaucoma patients) using high-throughput single nucleus RNA sequencing. The transcriptional signatures of glaucomatous RGCs and ONH cells will be cross compared with that of a multiple mouse models of glaucoma. We expect this to significantly improve our understanding of the molecular basis of glaucoma and uncover novel genetic targets for the development of neuroprotective therapies. Furthermore, this proposal details a career development plan for the principal investigator of the proposed study to build a strong and sustainable research program in an academic research institute as an independent investigator. The mentored phase of this award will be supervised by a multidisciplinary advisory team specialized in retinal neurobiology, computational biology, neuro-glia communication, and glaucoma. The proposed research and training plans will take place in the Center for Brain Science at Harvard University and the F.M. Kirby Neurobiology Center at Boston Children's Hospital.

项目概要青光眼是美国和全世界不可逆转失明的主要原因之一。神经节细胞（RGC）——向大脑传递视觉信息的神经元——是青光眼的一个标志。眼内压 (IOP) 升高是大多数类型青光眼的主要危险因素，降低眼压仍然有效减缓视力丧失的唯一有效治疗方法然而，许多眼压看似得到控制的患者仍然如此。经历进行性视力丧失，突显了对神经保护疗法的需求未得到满足无论是单独使用还是与降低眼压的药物联合使用，保持 RGC 的活性是开发的一个关键障碍。神经保护疗法缺乏对 RGC 死亡、神经保护和青光眼的动物模型未能捕捉到人类青光眼的一些特征，包括渐进性。视力丧失的进展和视神经乳头（ONH）结缔组织的重塑。迫切需要直接研究人类青光眼中 RGC 死亡的机制。该提案旨在通过对死后人类视网膜的直接分析来揭示此类分子机制。黄斑和外周 RGC 的转录谱以及位于 ONH 的所有细胞都将从使用高通量基因和临床定义的人类供体（健康对照和青光眼患者）青光眼 RGC 和 ONH 细胞的转录特征将是与多种青光眼小鼠模型进行交叉比较，我们预计这将显着改善我们的结果。了解青光眼的分子基础并发现新的遗传靶标此外，该提案还详细介绍了校长的职业发展计划。拟议研究的研究者，旨在在学术研究中建立强大且可持续的研究计划该奖项的指导阶段将由一名独立调查员进行监督。专门从事视网膜神经生物学、计算生物学、神经胶质细胞的多学科顾问团队拟议的研究和培训计划将在脑中心进行。哈佛大学科学和波士顿儿童医院 F.M.柯比神经生物学中心。