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Cell Specific RIPK3 signaling after traumatic brain injury in mice

小鼠脑外伤后细胞特异性 RIPK3 信号转导

基本信息

批准号：
10199405
负责人：
MICHAEL J WHALEN
金额：
$ 42.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10199405
关键词：
Acute Aging Apoptosis Astrocytes Behavior Bone Marrow Brain Brain Injuries CASP8 gene CD95 Antigens Cell Death Cell Fraction Cells Cessation of life Chimera organism Chronic Chronic Phase Clinical Clinical Trials Cognitive deficits Cortical Contusions Data Detergents Disease Down-Regulation Endothelial Cells Endothelium Etiology Event Experimental Models Fluorescence-Activated Cell Sorting Gene Expression Genetic Goals HMGB1 gene Hippocampus (Brain)Histology Human Immune Immunoprecipitation Impairment Inflammasome Inflammation Inflammation Mediators Inflammatory Injury Interleukin-1 beta Knock-out Knockout Mice Lead Lesion Link MAP Kinase Gene MAP3K7 gene Mediating Methodology Microglia Modeling Molecular Motor Mus Necrosis Nerve Degeneration Neurodegenerative Disorders Neurologic Dysfunctions Neurological outcome Neuronal Injury Neurons Outcome Pathway interactions Peripheral Phosphorylation Phosphotransferases Population Protein Kinase Protein-Serine-Threonine Kinases Proteins Publishing Quality of life RIPK1 gene RIPK3 gene Reagent Regulation Resolution Role Signal Transduction Survivors Systemic disease TBI Patients TBK1 gene TLR4 gene TNF gene TNFRSF1A gene TRADD gene Tamoxifen Testing Traumatic Brain Injury Tumor Necrosis Factor Receptor Tumor-infiltrating immune cells Ubiquitination Up-Regulation Western Blotting Work age related neurodegeneration brain cell brain tissue cell type cognitive function controlled cortical impact experimental study functional outcomes genetic regulatory protein grasp improved improved outcome inhibitor/antagonist injured macrophage morris water maze motor deficit multicatalytic endopeptidase complex neuron loss new therapeutic target novel object recognition p38 Mitogen Activated Protein Kinase proteostasis recombinase-mediated cassette exchange response stroke model therapeutic target tool

项目摘要

Receptor interacting protein kinases (RIPK)-1 and -3 are serine-threonine kinases that regulate apoptosis, necrosis, and inflammation. RIPKs mediate programmed necrosis via RIPK1-RIPK3-MLKL necrosome assembly, and apoptosis via the ripoptosome involving FLIP, caspase-8, TRADD, and RIPK3, among others. RIPK1 inhibitors are currently in human clinical trials for several systemic diseases. In contrast, RIPK3 has been less studied in part because clinically acceptable RIPK3 inhibitors are not yet available. Building on our prior studies showing improved neurological outcome in mice deficient in TNF and Fas receptor (upstream activators of RIPK3), we used genetic tools to interrogate a possible role for RIPK3 in a mouse controlled cortical impact (CCI) model. Mice lacking RIPK3 had improved motor and cognitive function after CCI, and greater protection in cognitive function tests than RIPK1 kinase dead or MLKL knockout mice, suggesting a unique role for RIPK3- independent of necroptosis because acute neuronal cell death or lesion volume was not reduced by RIPK3 knockout. Using immunopanning to isolate specific brain cell populations, we found the highest levels of RIPK3 expression in endothelium and immune cells. RIPK3 KO mice had reduced HMGB1 release after CCI, reduced interleukin-1 beta processing in brain tissue and endothelial cells, and maintained K48 ubiquitination of neuronal proteins and brain TBK1 levels- mechanisms that have previously been shown to modulate outcome after CCI and contribute to neurodegeneration in aging-related neurodegenerative diseases. We hypothesize that RIPK3 signaling in endothelial and immune cells induces neurological dysfunction after cerebral contusion by activating multiple acute inflammation pathways and is a potential therapeutic target to improve outcome. To test this hypothesis we propose three specific aims: Aim 1, to identify upstream mechanisms regulating RIPK3 activation in specific brain cell types after CCI in mice, using immunopanning and FACS to isolate specific brain cell types; Aim 2, to define cell-specific functional roles for RIPK3 in brain vs. peripheral immune cells using bone marrow chimeras and inducible/conditional RIPK3 knockout mice; and Aim 3, to identify mechanisms downstream of RIPK3 that might contribute to neurodegeneration in the chronic period after TBI.

受体相互作用蛋白激酶(RIPK)-1和-3是丝氨酸-苏氨酸激酶，可调节细胞凋亡；