权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Arterial Vasoregulation by Notch Signaling

通过 Notch 信号调节动脉血管

基本信息

批准号：
10619623
负责人：
AARON PROWELLER
金额：
$ 52.33万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619623
关键词：
Acute Adult Animal Disease Models Animals Arteries Biological Assay Blood Pressure Blood Vessels Blood flow Cell Communication Cell Compartmentation Chronic Clinical Coupled DNA Sequence Alteration Development Dilator Disease Endothelial Cells Endothelium Enzymes Equilibrium Exhibits Foundations Functional disorder Gene Expression Generations Goals Health Human Hypertension Hypotension Impairment In Vitro Instruction Knowledge Laboratories Left Ligands Measures Mediating Molecular Molecular Profiling Morbidity - disease rate Mus Muscle function Myography Myosin ATPase Myosin Light Chain Kinase Myosin Light Chains Pathway interactions Peripheral Phenotype Phosphorylation Phosphotransferases Physiologic intraventricular pressure Physiological Physiology Post-Translational Protein Processing Production Protein Dephosphorylation Regulation Relaxation Resistance Role Second Messenger Systems Sepsis Signal Induction Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Smooth Muscle Myosins Stimulus Stroke Syndrome Systemic blood pressure Testing Therapeutic Vascular Diseases Vascular Smooth Muscle Vascular resistance Vasodilation blood pressure regulation cardiovascular risk factor desensitization hemodynamics in vivo loss of function mortality mouse model myosin phosphatase notch protein novel novel therapeutic intervention pharmacologic pressure receptor receptor function response transmission process vasoconstriction

项目摘要

PROJECT SUMMARY/ABSTRACT Vascular smooth muscle (SM) and endothelial cells (EC) coordinate the molecular signals governing arterial vasoreactivity. The balance of constrictor and relaxant signals establishes vessel tone and directly influences systemic blood pressure in health and disease. Our laboratory has uncovered novel and paradoxical roles for Notch signaling in the vessel wall that influence arterial function. Specifically, SM Notch receptors triggered by SM Jagged1 ligand promote myosin light chain kinase (MLCK) expression and Ca2+ sensitization inducing myosin light chain (MLC) phosphorylation, the molecular signature of force production. Mice lacking SM Jagged1 feature dysregulated blood pressure and pressor responses and arteries exhibit impaired force generation. In contrast, EC Dll4 ligand stimulates expression of SM MYPT1, the regulatory subunit of myosin phosphatase (MP), favoring dephosphorylation of MLC and a relaxant phenotype. Moreover, EC Dll4-deficient arteries yield vasorelaxation deficits in a novel NO-independent manner. Together, these findings underscore instructional Notch signaling through heterotypic (EC-SM) and homotypic (SM-SM) cell interactions in the vessel wall and provide new knowledge in the molecular determinants of vasoregulation. The overall goal in this new project proposal is to define the physiologically relevant Notch ligand/receptor that modulates distinct arterial functions. In Aim 1, we determine the contribution of both SM and EC Jagged1 ligand and Notch1 receptor in regulation of constrictor and hemodynamic responses in vascular health and disease animal models. Aim 2 delineates the physiological role and mechanism of EC Dll4 ligand in mediating arterial relaxation. Finally, Aim 3 examines the molecular basis for Notch signaling-dependent control of myosin phosphatase activity via Ca2+ sensitization and/or desensitization. Experimental approaches include a full spectrum of in vivo, ex vivo and in vitro vascular analyses necessary for understanding relevant physiology and novel molecular mechanisms through which Notch pathway components regulate arterial function.

项目总结/文摘