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CCN1-induced Senescence in the Cerebral Vasculature

CCN1 诱导的脑血管衰老

基本信息

批准号：
10627740
负责人：
Jose Felix Moruno Manchon
金额：
$ 19.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627740
关键词：
Aging Bilateral Binding Binding Proteins Blood - brain barrier anatomy Brain Carotid Stenosis Cell Aging Cell Cycle Cell Cycle Progression Cell Proliferation Cell Separation Cell physiology Cell secretion Cells Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Cognitive deficits Coupled Cysteine DNA DNA Damage Data Dementia Disease Down-Regulation Endothelial Cells Endothelium Extracellular Matrix Proteins FMR1 Fibroblasts Functional disorder G-Quartets Gait Gene Targeting Genetic Transcription Guanine Heterochromatin Impairment Integrin alpha6beta1 Integrins Ligands Link Measures Mediating Membrane Messenger RNA Microscopy Modeling Molecular Motor Mus Operative Surgical Procedures Pathologic Patients Permeability Phenotype Play Predisposition Protein Deficiency Protein Secretion Proteins RNA RNA Splicing RNA-Binding Proteins Ribosomes Role Scheme Secondary to Signal Pathway Structure System Techniques Testing Tissues Translational Repression Translations Tumor Suppressor Proteins Up-Regulation Viral Vector adhesion receptor aged aging brain blood-brain barrier disruption brain endothelial cell cancer cell cell injury cerebral hypoperfusion cerebrovascular pathology cognitive function conditioned fear cysteine rich protein dementia risk design gray matter motor deficit mouse model mutant negative affect novel object recognition overexpression prevent senescence vascular cognitive impairment and dementia vector white matter

项目摘要

Project Summary Vascular contributions to cognitive impairment and dementia (VCID) includes a number of different disorders identified by cognitive deficits secondary to cerebrovascular pathology. Senescence in the cerebral endothelium has been proposed as a mechanism that can drive blood brain barrier disruption (BBB), which precedes VCID. However, the mechanisms that drive endothelial cells to senescence are not fully understood. Guanine-quadruplex (G4) is a non-canonical secondary structure formed in G-rich sequences in DNA and RNA. Importantly, G4 stabilization promotes cellular senescence. Particularly, stabilization of G4s in mRNA (rG4s) stalls ribosomes in the elongation stage and blocks translation. This mechanism is promoted by rG4- binding proteins. Fragile X mental retardation protein (FMRP) binds to the rG4 of tumor suppressors and components of signaling pathways involved in senescence. FMRP deficiency has been associated with senescence in different tissues. We found that overexpressing FMRP in cultured cerebral endothelial cells (CEC) mitigated DNA damage, an important cause of cell senescence. We found that G4 stabilization promoted endothelial senescence and enhanced the levels of Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), a matricellular protein secreted by endothelial cells in the brain. CCN1 is considered a component of the senescence-associated secretory phenotype (SASP). In fibroblasts, CCN1 induces senescence by binding to integrin α6β1. In our study, we will use bilateral carotid artery stenosis (BCAS) that induces chronic cerebral hypoperfusion and models VCID in mice. We found that BCAS mice showed enhanced levels of G4s, CCN1 and senescence markers. We hypothesize that the endothelial senescence associated with G4 stabilization could be mitigated in mice and hence prevent BBB disruption and cognitive deficits. To test our hypothesis, we propose two aims: In Aim 1, we will selectively target the brain endothelium of young mice with a vector encoding a mutant form of CCN1 that cannot bind to α6β1. We will measure motor and cognitive function, and BBB permeability, and senescence in the brain. In Aim 2, we will determine if upregulating FMRP mitigates motor and cognitive deficits, BBB impairment, and senescence in the cerebral vasculature of aged BCAS mice. Overall, this study proposes two independent strategies to mitigate VCID-associated phenotypes induced by senescence in the cerebrovasculature: impeding the CCN1-α6β1binding in the cerebral endothelium; and upregulating FMPR specifically in the brain vasculature of mice.

项目总结