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.

项目摘要来自人类青光眼研究和实验模型的研究不断增长的信息支持了胶质驱动的神经炎症会对残留神经节细胞（RGC）somas，轴突和突触及其治疗调节可以提供宽度的神经保护作用。我们从关于青光眼中神经炎症的最新研究导致了我们旨在在该项目中检验的新假设。显然，CFLIP用作caspase-8介导的细胞死亡/生存/炎症之间的分子切换通过TNFR，TLR和炎性体的途径，我们的第一个特定目标将测试是否有条件删除星形胶质细胞CFLIP可以抑制炎症结果caspase-8/cflip相互作用，并防止/逆转实验青光眼中的炎症/神经毒性星形胶质细胞表型。我们希望删除cflip 星形胶质细胞将有选择地靶向炎症/神经毒性（A1）星形胶质细胞（因为这些细胞是针对的通过TNF-α/TNFR，FAS/FASL，TLR和炎症体的炎症caspase-8功能，并将提供免疫调节（无需冒着神经胶质神经支持功能）。除了CFLIP，我们还将有选择地定位 CFLIPL还可以确定炎症结果和细胞脂肪决策的同工型特异性差异。我们将分析形态和分子对星形胶质CFLIP（或CFLIPP）缺失的空间和临时响应视网膜和视神经星形胶质细胞的分析，包括炎症反应，A1/A2星形胶质细胞分布，细胞死亡（凋亡/坏死性）和神经支持功能。消除星形胶质细胞驱动的炎症可以保护RGC免受实验青光眼的炎症损伤。我们的特定目标2将检验此假设通过分析神经元存活（通过RGC轴突/SOMA计数）和功能（通过PERG）。星形胶质细胞和小胶质细胞紧密相互作用和调节彼此的表型和免疫功能。我们最近的研究发现支持星形胶质细胞因子反应可能会塑造实验青光眼中的小胶质细胞反应。我们的因此，特定的目标3旨在测试CFLIP（或CFLIPP）的神经胶质亚型特异性缺失是否会影响神经炎症期间，星形胶质细胞和小胶质细胞之间的个人贡献和串扰。我们将分析小胶质细胞的反应（包括M1/M2转换），以及星形胶质细胞的响应以及星形胶质细胞反应（包括A1/A2分布）到不同站点/时间点的小胶质细胞缺失。纵向分析也将包括少突胶质细胞和müller神经胶质反应。通过分析细胞类型特异性响应（包括分离的神经胶质亚型的分子响应）对靶向胶质亚型的小鼠模型的分子响应，该项目将重视神经胶质CFLIP作为预防/反向神经退行性炎症的免疫调节治疗靶标实验青光眼。预计该项目的结果在其他研究中也将广泛有用眼/神经退行性/神经炎症性疾病，老化，干细胞/轴突再生和癌症研究。