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cAMP signaling in vascular smooth muscle in health and disease

健康和疾病状态下血管平滑肌中的 cAMP 信号传导

基本信息

批准号：
10370716
负责人：
Manuel F Navedo
金额：
$ 65.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370716
关键词：
Address Adenosine Monophosphate Adenylate Cyclase Animal Model Arteries Blood Vessels Blood flow Caliber Cardiovascular Diseases Cells Complex Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Disease Distributional Activity Enzymes Generations Glucose Health Human Hypertension Image Imaging Techniques Knowledge Link Mediating Membrane Microdomains Mission Modeling Mus Muscle Contraction Muscle function Myography Pathologic Pathology Periodicity Physiological Premenopause Production Property Proteins Public Health Regulation Relaxation Sarcoplasmic Reticulum Second Messenger Systems Signal Transduction Site Stimulus Testing United States National Institutes of Health Vascular Smooth Muscle Vasodilation Woman biological sex blood flow measurement clinically significant diabetic patient extracellular health goals in silico in vivo innovation insight male new therapeutic target non-diabetic novel novel therapeutic intervention phosphoric diester hydrolase receptor segregation sensor sex tool treatment strategy

项目摘要

Abstract . The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) is essential for regulating vascular smooth muscle (VSM) function, including reactivity. The dogma that cAMP signaling in VSM only mediates relaxation was recently challenged by our observation that glucose induces a subtle cAMP synthesis that promotes contraction. These results suggest that cAMP versatility to regulate VSM reactivity to diverse stimuli depends on their spatially confined properties within the cell, of which little is known. Moreover, no studies have examined how cAMP pools are modulated by biological sex and its functional implications in VSM in health and disease. Studies here will therefore address these key knowledge gaps. By leveraging the use of a sophisticated toolkit in human and mouse VSM, exciting preliminary data is generated in support of the central hypothesis that the production of discrete cAMP pools is essential for integrating receptor-dependent cAMP signaling to control VSM reactivity in health and disease, and this is dependent on biological sex. This hypothesis will be tested in three specific aims. Aim 1 is to test the hypothesis that Gs protein-coupled receptors (GsPCRs) induce sex- specific discrete cAMP pools in VSM. Aim 2 is to test the hypothesis that GsPCRs cellular segregation triggers distinct sex-specific discrete cAMP pools in VSM. Finally, Aim 3 is to test the hypothesis that discrete cAMP pools in VSM are disrupted in diabetes and hypertension (HTN). The proposal has high basic, translational and clinical significance as it will reveal 1) new insight into discrete cAMP pools in VSM, 2) their influence by biological sex in health and disease, and 3) opportunities to identify novel targets and develop new therapeutic strategies.

摘要。