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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' 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

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 为了响应PA-20-272要求为NIH提供以阿尔茨海默氏症为重点的行政补充 不关注阿尔茨海默氏症(AD)的赠款，此应用程序建议扩大 现有奖项(5个R01 EY031696-02)用于识别AD的新发病机制和生物标志物。 目前，对于阿尔茨海默病还没有确定的治愈方法或疾病修正疗法，这主要是由于缺乏 对该病的发病机制有清晰的认识。眼睛提供了了解大脑许多方面的窗口 功能和健康。在AD中观察到了广泛的与眼睛相关的并发症。其中包括 视网膜神经节细胞(RGC)丢失和主要细胞类型--视网膜神经纤维层(RNFL)变薄 受青光眼影响。新出现的证据也表明分子机制之间存在重叠。 青光眼和阿尔茨海默病。我们最近报道了一种新的涉及系统T细胞的免疫成分 青光眼发病机制的潜在反应，这标志着 神经退行性变。我们证明了青光眼患者的慢性神经变性与 通过诱导针对热休克蛋白的CD4+T辅助细胞1(Th1)的系统反应 (热休克蛋白)。对神经元的急性侮辱和应激，如与缺血、损伤或升高有关的侮辱和应激 眼内压，引起小胶质细胞激活，启动HSP特异性T细胞反应 到神经元丧失的延长阶段。此外，通过当前裁决获得的数据(EY031696) 进一步表明，不仅原发性开角型青光眼的患者表现出显著的增加 HSP特异性T细胞在外周血中的频率与对照组相比，但HSP- 特异性T细胞计数与RNFL变薄有关。这些结果证明了人类的相关性 全身性T细胞介导的青光眼神经元损伤机制。积累证据 显示外周活化的CD4+T细胞可以在血脑屏障完好的情况下进入中枢神经系统。 总之，这些都导致了我们的假设的扩展，即类似的免疫机制包括 青光眼的全身性T细胞反应在AD患者的神经退行性变中起作用。因此，我们 建议扩大目前的研究，以批判性地研究热休克蛋白特异性Th1细胞在动物中的作用 模型和人类阿尔茨海默病患者。我们会问：(1)如果小鼠和人类AD患者表现出增加 外周血中HSP特异性T细胞频率与对照组的比较，以及(2)如果过继转移 从阿尔茨海默病小鼠中提取的热休克蛋白特异性T细胞的数量增加会加剧受体小鼠大脑中的阿尔茨海默病病理。这个 拟议的研究可能会揭示AD发病机制的新见解，以及对外周血的识别 血清生物标记物可能导致筛查AD和/或高危个体的新诊断方法 监测疾病进展。