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Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

青光眼发病机制中的先天性和适应性免疫

基本信息

批准号：
10715564
负责人：
Dong Feng Chen
金额：
$ 50.44万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715564
关键词：
Acceleration Acute Address Administrative Supplement Adoptive Transfer Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Animal Model Apoptosis Award Axon Biological Markers Blood Blood - brain barrier anatomy Boston Brain CD4 Positive T Lymphocytes Cell Count Cells Chronic Correlation Studies Data Deposition Development Diagnostic Procedure Disease Disease Progression Education Enzyme-Linked Immunosorbent Assay Exhibits Eye Flow Cytometry Frequencies Glaucoma Grant HSPB1 gene Health Heat shock proteins Human Immune Immunize Individual Injury Interferon Type II Investigation Ischemia Link Mediating Methods Molecular Monitor Mus Natural Immunity Nerve Degeneration Neuronal Injury Neurons Newly Diagnosed Pathogenesis Pathology Patients Peripheral Phase Physiologic Intraocular Pressure Play Primary Open Angle Glaucoma Protein Family Regulatory T-Lymphocyte Reporting Research Research Subjects Retina Retinal Ganglion Cells Role Serum Signal Transduction Splenocyte Stress T cell infiltration T cell response T cell therapy T-Cell Activation T-Lymphocyte Tail Testing Thinness United States National Institutes of Health Universities Veins Work abeta deposition abeta toxicity adaptive immunity biological adaptation to stress blood-brain barrier penetration cell mediated immune response cell type cognitive function comparison control cytokine draining lymph node experience glial activation human subject inhibitor innovation insight monocyte mouse model neural neuron loss novel novel diagnostics novel therapeutics peripheral blood progressive neurodegeneration recruit response retinal nerve fiber layer screening sex synaptic function

项目摘要

ABSTRACT In responding to the PA-20-272 that calls for Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's Disease (AD), this application proposes to expand on the existing award (5 R01 EY031696-02) to the identification of novel pathogenesis and biomarkers of AD. There is, at present, no established cure or disease-modifying treatment for AD, largely due to the lack of clear understanding of the disease pathogenesis. The eyes provide a window into many aspects of brain function and health. Extensive eye-related complications have been observed in AD. These include the loss of retinal ganglion cells (RGCs) and thinning of the retinal nerve fiber layer (RNFL), the main cell type affected in glaucoma. Emerging evidence also suggests an overlap between the molecular mechanisms of glaucoma and those of AD. We recently reported a novel immune component involving systemic T cell responses underlying the pathogenesis of glaucoma, that signifies a paradigm shift concept in neurodegeneration. We demonstrated that chronic neurodegeneration in glaucoma is critically associated with the induction of systemic responses of CD4+ T helper 1 (Th1) cells specific to heat shock proteins (HSPs). Acute insults and stress to neurons, such as those associated with ischemia, injury, or elevated intraocular pressure, evoke microglial activation that initiates HSP-specific T cell responses to contribute to a prolonged phase of neuron loss. Moreover, data acquired through the current award (EY031696) showed further that not only patients with primary open angle glaucoma exhibited significantly increased frequencies of HSP-specific T cells in the peripheral blood compared to control subjects, but the HSP- specific T cell counts correlated with the thinning of RNFL. These results demonstrate the human relevance of a systemic T cell-mediated mechanism in glaucomatous neuronal damage. Accumulating evidence showed that peripherally activated CD4+ T cells could enter the CNS with an intact blood-brain-barrier. Together, these have led to the extension of our hypothesis that the similar immune mechanism involving systemic T cell responses in glaucoma is at the play to perpetuate neurodegeneration in AD. We therefore propose to expand the current studies to critically examine the roles of HSP-specific Th1 cells in animal models and human patients with AD. We will ask: (1) if mice and human patients with AD exhibit increased HSP-specific T cell frequencies in the peripheral blood compared to controls, and (2) if adoptive transfer of HSP-specific T cells taken from AD mice exacerbates AD pathology in the recipient mouse brains. The proposed studies may uncover novel insights into AD pathogenesis, and identification of peripheral blood and serum biomarkers may lead to new diagnostic method for screening individuals at risk for AD and/or monitoring disease progression.

摘要