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.

抽象的 在回应呼吁阿尔茨海默氏症的PA-20-272时 不关注阿尔茨海默氏病（AD）的赠款，该申请提议扩展 现有奖项（5 R01 EY031696-02）鉴定了新型的发病机理和AD生物标志物。 目前，目前尚无既定的治愈方法或改良疾病的AD治疗方法，这主要是由于缺乏 对疾病发病机理的清晰了解。眼睛为大脑的许多方面提供了一个窗口 功能和健康。在AD中观察到了广泛的与眼睛有关的并发症。这些包括 视网膜神经节细胞（RGC）的丧失和视网膜神经纤维层（RNFL）的稀疏（RNFL）（主要细胞） 受到青光眼的影响。新兴的证据还表明分子机制之间有重叠 青光眼和AD的青光眼。我们最近报道了一种涉及全身T细胞的新型免疫成分 青光眼发病机理的背后的反应表示表示范式转移概念 神经变性。我们证明了青光眼中的慢性神经退行性关系密切相关 随着CD4+ T辅助1（Th1）细胞的全身反应的诱导 （HSP）。对神经元的急性侮辱和压力，例如与缺血，损伤或升高有关的神经元 眼内压，引起小胶质细胞激活，启动HSP特异性T细胞反应有助于 直到长时间的神经元丧失阶段。此外，通过当前奖项获得的数据（EY031696） 进一步表明，不仅具有原发性开角青光眼的患者表现出显着增加 与对照组相比，外周血中HSP特异性T细胞的频率 特定的T细胞计数与RNFL的变薄相关。这些结果证明了人类的相关性 青光眼神经元损伤中的全身T细胞介导的机制。积累证据 表明外周活化的CD4+ T细胞可以使用完整的血脑屏障进入中枢神经系统。 共同导致了我们假设的扩展，即类似的免疫机制涉及 青光眼中的系统性T细胞反应正在发挥，以使AD中的神经退行性永存。因此，我们 提议扩展当前的研究，以批判性地检查HSP特异性Th1细胞在动物中的作用 AD模型和人类患者。我们会问：（1）是否有小鼠和人类AD患者表现出来 与对照组相比，外周血中的HSP特异性T细胞频率，以及（2） 从AD小鼠中获取的HSP特异性T细胞加剧了受体小鼠大脑中的AD病理。这 拟议的研究可能会发现对AD发病机理的新见解和外周血的鉴定 血清生物标志物可能会导致新的诊断方法，以筛查有AD和/或 监测疾病进展。