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

• 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
• 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

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.

项目摘要 青光眼是美国和世界范围内不可逆失明的主要原因之一。视网膜脱落 神经节细胞（RGC）--将视觉信息传递到大脑的神经元--是青光眼的标志。 眼内压升高（IOP）是大多数类型青光眼的主要危险因素，降低眼压仍然是一个重要的因素。 唯一有效的治疗方法来减缓视力下降。然而，许多看似控制了IOP的患者仍然 经历进行性视力丧失，强调了对神经保护治疗的未满足需求， 保持RGC存活，无论是单独使用还是与降低IOP的药物联合使用。发展的一个关键障碍 神经保护治疗缺乏对RGC死亡，神经保护和 生存青光眼的动物模型未能捕捉到人类青光眼的一些特征，包括渐进性青光眼。 视力丧失的进展和视神经乳头（ONH）结缔组织的重塑。由此可见，有一 迫切需要直接研究人类青光眼中RGCs死亡的机制。这 该提案旨在通过对死后人类视网膜的直接分析来揭示这种分子机制。的 黄斑和外周RGC的转录谱，以及位于ONH的所有细胞将从 基因和临床上定义的人类供体（健康对照和青光眼患者）， 单核RNA测序。将对青光眼RGC和ONH细胞的转录特征进行分析。 交叉比较多个小鼠青光眼模型的结果。我们希望这将大大改善我们的 了解青光眼的分子基础，并发现新的遗传靶点， 神经保护疗法此外，该提案详细说明了校长的职业发展计划 拟议研究的调查员，以建立一个强大的和可持续的研究计划，在学术研究 作为独立调查员。该奖项的指导阶段将由一名 多学科咨询团队，专门从事视网膜神经生物学、计算生物学、神经胶质 沟通和青光眼。拟议的研究和培训计划将在脑中心进行 科学在哈佛大学和F.M.波士顿儿童医院Kirby神经生物学中心