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：
10532163
负责人：
Manuel F Navedo
金额：
$ 65.42万
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/10532163
关键词：
Address Adenylate Cyclase Animal Model Arteries Blood Vessels Blood flow Cardiovascular Diseases Cells Complex Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Diameter Disease Enzymes Generations Glucose Health Human Hypertension Image Imaging Techniques Knowledge Link Mediating Membrane Microdomains Mission Modeling Mus Muscle Contraction Muscle function Myography Pathologic Pathology 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.

抽象的。第二信使 3',5'-环磷酸腺苷 (cAMP) 对于调节血管至关重要平滑肌 (VSM) 功能，包括反应性。 VSM 中 cAMP 信号传导仅介导的教条最近，我们观察到葡萄糖诱导了微妙的 cAMP 合成，这对放松提出了挑战。促进收缩。这些结果表明 cAMP 具有调节 VSM 对不同刺激的反应性的多功能性取决于它们在细胞内的空间限制特性，对此我们知之甚少。此外，还没有研究表明检查了 cAMP 池如何通过生物性别进行调节及其在健康和 VSM 中的功能意义疾病。因此，这里的研究将解决这些关键的知识差距。通过利用复杂的在人类和小鼠 VSM 工具包中，生成了令人兴奋的初步数据来支持中心假设：离散 cAMP 池的产生对于整合受体依赖性 cAMP 信号传导以控制 VSM 在健康和疾病中的反应性，这取决于生物性别。该假设将在三个具体目标。目标 1 是检验 Gs 蛋白偶联受体 (GsPCR) 诱导性行为的假设 VSM 中特定的离散 cAMP 池。目标 2 是检验 GsPCR 细胞分离触发的假设 VSM 中不同性别特异性的离散 cAMP 池。最后，目标 3 是检验离散 cAMP 的假设 VSM 池在糖尿病和高血压 (HTN) 中被破坏。该提案具有较高的基础性、转化性和临床意义，因为它将揭示 1) 对 VSM 中离散 cAMP 池的新见解，2) 它们受生物学影响健康和疾病中的性，3) 确定新目标和开发新治疗策略的机会。