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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.

项目总结