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.

项目摘要青光眼是美国和全球不可逆失明的主要原因之一。视网膜丧失神经节细胞（RGC）（将视觉信息传达给大脑的神经元）是青光眼的标志。眼内压（IOP）是大多数类型的青光眼的主要危险因素，并将其降低视力丧失放缓的唯一有效治疗方法。但是，许多看似控制IOP的患者仍然体验逐步丧失视力，强调对神经保护疗法的未满足的需求将RGC保持活力，无论是单独还是与降低IOP的药物结合使用。发展的关键障碍神经保护理论是缺乏对RGC死亡，神经保护和生存。青光眼的动物模型无法捕获人类青光眼的某些特征，包括等级视力丧失的进展和视神经头（ONH）连接的时机的重塑。那有一个直接研究RGC在人青光眼中死亡的机制的迫切需要。这提案旨在通过直接分析死后人类视网膜的直接分析来揭示这种分子机制。这黄斑和周围RGC的转录曲线以及所有位于ONH的单元使用高通量单核RNA测序。青光眼RGC和ONH细胞的转录特征将是与青光眼的多个小鼠模型相比。我们希望这将大大改善我们的了解青光眼的分子基础，并发现新的遗传靶标的开发神经保护疗法。此外，该建议详细介绍了校长的职业发展计划拟议研究的研究者在学术研究中建立强大而可持续的研究计划研究所作为独立调查员。该奖项的重要阶段将由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glia 交流和青光眼。拟议的研究和培训计划将在大脑中心进行哈佛大学科学和F.M.波士顿儿童医院的柯比神经生物学中心。