Transcriptional signatures of glaucomatous retinal and optic nerve head cells

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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.