Modulation of Neuroinflammation in Glaucoma

青光眼神经炎症的调节

基本信息

批准号：
10707877
负责人：
Gulgun TEZEL
金额：
$ 41.13万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707877
关键词：
Adverse effects Affect Aging American Apoptosis Apoptotic Astrocytes Axon Biological Response Modifiers Blindness CASP8 gene Cell Death Cells Data Disease Dissection Ensure Experimental Designs Experimental Models Exposure to Gene Targeting Glaucoma Glial Fibrillary Acidic Protein Human Individual Inflammaging Inflammasome Inflammation Inflammatory Inflammatory Response Injury Mediating Medical Research Methodology Methods Microglia Modeling Molecular Molecular Analysis Morphology Mouse Strains Muller&apos s cell Mus Nerve Degeneration Neuroglia Neurons Oligodendroglia Optic Disk Optic Nerve Outcome Pathway interactions Phenotype Pilot Projects Play Process Protein Isoforms Regenerative research Regulation Reporting Research Retina Retinal Ganglion Cells Risk Sampling Shapes Site Synapses TNF gene Testing Therapeutic Time Toxic effect Transcription Coactivator Tumor Necrosis Factor Receptor Vision anticancer research axon regeneration cell type cytokine design experimental study immune function immunomodulatory therapies immunoregulation insight longitudinal analysis mouse model nerve injury neuroinflammation neuronal cell body neuronal survival neuroprotection neurotoxic prevent promoter prospective response retinal apoptosis side effect stem cells treatment strategy

项目摘要

PROJECT SUMMARY Growing information from the studies of human glaucoma and experimental models supports that glia-driven neuroinflammation creates an additional damaging force on retinal ganglion cell (RGC) somas, axons, and synapses, and its therapeutic modulation can provide widespread neuroprotection. Our accumulated data from recent studies of neuroinflammation in glaucoma led to our new hypotheses that we aim to test in this project. Evidently, cFLIP functions as a molecular switch between caspase-8-mediated cell death/survival/inflammation pathways through TNFRs, TLRs, and inflammasome, Our first Specific Aim will test whether conditional deletion of astroglial cFLIP can inhibit the inflammatory outcomes caspase-8/cFLIP interaction and prevent/reverse the inflammatory/neurotoxic astrocyte phenotype in experimental glaucoma. We expect that deletion of cFLIP in astroglia will selectively target inflammatory/neurotoxic (A1) astrocytes (because these cells are primed for inflammatory caspase-8 functions through TNF-α/TNFR, Fas/FasL, TLRs, and inflammasome) and will provide immunomodulation (without risking the glial neurosupport functions). Besides cFLIP, we will selectively target cFLIPL to also determine isoform-specific differences in inflammatory outcomes and cell fate decisions. We will analyze spatial and temporal responses to astroglial cFLIP (or cFLIPL) deletion by morphological and molecular analysis of retina and optic nerve astroglia, including inflammatory responses, A1/A2 astrocyte distribution, cell death (apoptosis/necroptosis), and neurosupport functions. Elimination of astroglia-driven inflammation can protect RGCs against inflammatory injury in experimental glaucoma. Our Specific Aim 2 will test this hypothesis by analysis of neuron survival (by RGC axon/soma counting) and function (by PERG). Astroglia and microglia closely interplay and regulate each other’s phenotype and immune functions. Our recent research findings also supported that astroglial cytokine responses may shape microglia responses in experimental glaucoma. Our Specific Aim 3 is therefore designed to test whether glial subtype-specific deletion of cFLIP (or cFLIPL) can impact individual contributions and the cross-talk between astroglia and microglia during neuroinflammation. We will analyze microglia responses (including M1/M2 conversion) to astroglial deletions, and and astroglia responses (including A1/A2 distribution) to microglial deletions at different sites/time points. Longitudinal analysis will also include oligodendrocyte and Müller glia responses. Through the analysis of cell type-specific responses (including the molecular responses of isolated glial subtypes) to glial subtype-targeting mouse models, this project will value glial cFLIP as an immunomodulatory treatment target to prevent/reverse neurodegenerative inflammation in experimental glaucoma. Outcomes of this project are also expected to be widely useful in studies of other ocular/neurodegenerative/neuroinflammatory diseases, aging, stem cell/axon regeneration, and cancer research.

项目概要来自人类青光眼和实验模型的研究中越来越多的信息支持神经胶质细胞驱动神经炎症对视网膜神经节细胞 (RGC) 胞体、轴突和神经细胞产生额外的破坏力突触及其治疗调节可以提供广泛的神经保护作用。最近对青光眼神经炎症的研究得出了我们的新假设，我们打算在这个项目中测试这些假设。显然，cFLIP 作为 caspase-8 介导的细胞死亡/存活/炎症之间的分子开关发挥作用通过 TNFR、TLR 和炎症小体的途径，我们的第一个具体目标将测试是否有条件删除星形胶质细胞 cFLIP 可以抑制 caspase-8/cFLIP 相互作用的炎症结果，并预防/逆转我们预计 cFLIP 的缺失会导致实验性青光眼中的炎症/神经毒性星形胶质细胞表型。星形胶质细胞将选择性地靶向炎症/神经毒性 (A1) 星形胶质细胞（因为这些细胞已准备好炎症性 caspase-8 通过 TNF-α/TNFR、Fas/FasL、TLR 和炎症小体发挥作用），并将提供除了 cFLIP 之外，我们还将选择性地靶向免疫调节（不危及神经胶质神经支持功能）。 cFLIPL 还可以确定炎症结果和细胞命运决定中异构体特异性的差异。通过形态和分子分析星形胶质细胞 cFLIP（或 cFLIPL）缺失的空间和时间反应视网膜和视神经星形胶质细胞分析，包括炎症反应、A1/A2星形胶质细胞分布、细胞死亡（细胞凋亡/坏死性凋亡）和神经支持功能可以消除星形胶质细胞驱动的炎症。在实验性青光眼中保护 RGC 免受炎症损伤，我们的具体目标 2 将检验这一假设。通过分析神经元存活（通过 RGC 轴突/体细胞计数）和功能（通过 PERG）。我们最近的研究发现也密切相互作用并调节彼此的表型和免疫功能。支持星形胶质细胞因子反应可能影响实验性青光眼中小胶质细胞的反应。因此，特定目标 3 旨在测试 cFLIP（或 cFLIPL）的神经胶质亚型特异性删除是否会影响我们将研究神经炎症过程中的个体贡献以及星形胶质细胞和小胶质细胞之间的相互作用。分析小胶质细胞对星形胶质细胞缺失的反应（包括 M1/M2 转换）和星形胶质细胞反应（包括A1/A2分布）对不同位点/时间点的小胶质细胞缺失也将进行纵向分析。包括少突胶质细胞和穆勒神经胶质细胞反应通过分析细胞类型特异性反应（包括）。分离的神经胶质亚型的分子反应）对神经胶质亚型靶向小鼠模型的分子反应，该项目将重视胶质细胞 cFLIP 作为免疫调节治疗靶点，预防/逆转神经退行性炎症该项目的实验结果预计也将广泛用于其他研究。眼部/神经退行性/神经炎症疾病、衰老、干细胞/轴突再生和癌症研究。