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。 第二信使3 '，5'-环磷酸腺苷（cAMP）是调节血管紧张素转换酶活性所必需的。 平滑肌（VSM）功能，包括反应性。VSM中的cAMP信号转导仅介导 最近，我们观察到葡萄糖诱导一种微妙的cAMP合成， 促进收缩。这些结果表明cAMP调节VSM对不同刺激的反应性的多功能性 这取决于它们在细胞内的空间限制特性，对此知之甚少。此外，没有任何研究 研究了cAMP池如何被生物性别调节及其在健康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 工具包在人类和小鼠的VSM，令人兴奋的初步数据产生支持的中心假设， 离散cAMP池的产生对于整合受体依赖性cAMP信号传导至控制 VSM在健康和疾病中的反应性，这取决于生物性别。这一假设将在 三个具体目标。目的1是检验Gs蛋白偶联受体（GsPCR）诱导性行为的假设， VSM中特异性离散cAMP池。目的2是检验GsPCR细胞分离触发细胞内GsPCR信号转导的假设。 VSM中不同的性别特异性离散cAMP池。最后，目的3是检验离散cAMP 在糖尿病和高血压（HTN）中，VSM中的池被破坏。该提案具有很高的基础性、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，以及3）确定新靶点和开发新治疗策略的机会。