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

• 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
• 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

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 。 第二个Messenger 3'，5'-循环腺苷单磷酸盐（CAMP）对于调节血管至关重要 平滑肌（VSM）功能，包括反应性。 VSM中扎营发出信号的教条只会调解 最近，我们的观察结果挑战了放松 促进收缩。这些结果表明，cAMP多功能性调节VSM对各种刺激的反应性 取决于它们在细胞内的空间限制特性，该特性几乎没有知道。而且，没有研究 研究了营地池是如何通过生物学性别及其在VSM中的功能含义调节的， 疾病。因此，这里的研究将解决这些关键知识差距。通过利用精致的使用 人类和小鼠VSM中的工具包，生成令人兴奋的初步数据，以支持中心假设，即 离散营地池的产生对于整合受体依赖性cAMP传导至关重要 VSM在健康和疾病中的反应性，这取决于生物学性别。该假设将在 三个具体目标。目的1是检验GS蛋白偶联受体（GSPCR）的假设 VSM中的特定离散营地池。 AIM 2是测试GSPCRS细胞分离触发的假设 VSM中的独特性别分散营地池。最后，目标3是检验离散营地的假设 VSM中的池在糖尿病和高血压（HTN）中受到破坏。该提案具有高基本，翻译和 临床意义将揭示1）对VSM中离散营地池的新见解，2）生物学的影响 健康和疾病中的性别，以及3）确定新目标并制定新的治疗策略的机会。