Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults

靶向 Mas 受体治疗老年人糖尿病血管疾病

• 批准号: 10180827
• 负责人: Yagna Jarajapu
• 金额: $ 25.38万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180827
• 关键词: ACE2; Age; Aging; Blood Circulation; Blood Vessels; Bone Marrow; CD34 gene; Chimera organism; Clinical; Clinical Trials; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Early Intervention; Elderly; Functional disorder; Genetic; Health; Hyperglycemia; Impairment; Individual; Intervention; Knockout Mice; Ligands; Long-Term Effects; Mediating; Mediator of activation protein; Messenger RNA; Morbidity - disease rate; Mus; Natural regeneration; Outcome; Pathway interactions; Pharmacology; Prevalence; Prevention; Prevention approach; Pulmonary Heart Disease; Radiation Chimera; Receptor Activation; Renin-Angiotensin System; Risk; Role; Telomerase; Testing; Vascular Diseases; angiotensin I (1-7); base; blood damage; cardiovascular disorder risk; diabetic; endothelial stem cell; improved; ischemic injury; mortality; novel; overexpression; paracrine; preservation; prevent; receptor; receptor expression; repair function; repaired; reparative capacity; research clinical testing; sex; stem cell function; stem cells; therapeutic target; vascular injury; ACE2; Age; Aging; Blood Circulation; Blood Vessels; Bone Marrow; CD34 gene; Chimera organism; Clinical; Clinical Trials; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Early Intervention; Elderly; Functional disorder; Genetic; Health; Hyperglycemia; Impairment; Individual; Intervention; Knockout Mice; Ligands; Long-Term Effects; Mediating; Mediator of activation protein; Messenger RNA; Morbidity - disease rate; Mus; Natural regeneration; Outcome; Pathway interactions; Pharmacology; Prevalence; Prevention; Prevention approach; Pulmonary Heart Disease; Radiation Chimera; Receptor Activation; Renin-Angiotensin System; Risk; Role; Telomerase; Testing; Vascular Diseases; angiotensin I (1-7); base; blood damage; cardiovascular disorder risk; diabetic; endothelial stem cell; improved; ischemic injury; mortality; novel; overexpression; paracrine; preservation; prevent; receptor; receptor expression; repair function; repaired; reparative capacity; research clinical testing; sex; stem cell function; stem cells; therapeutic target; vascular injury

Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults Abstract Prevalence of diabetes is high among older adults and is expected to rise, and diabetes increases risk for cardiovascular disease. Accumulated evidence suggests that bone marrow-derived progenitor cells maintain vascular health and promote rapid repair following vascular injury. This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of EPCs from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore approaches that preserve EPC mobilization and function will prevent the development of vascular disease in older adults with diabetes. We hypothesize that the Mas receptor, the functional mediator of the vasoprotective axis of renin angiotensin system, confers mobilization and reparative functions in EPCs and that early intervention with MasR activation would preserve innate vasoprotection and prevents the development of vascular disease with aging and diabetes. This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of MasR, is down-regulated with aging and diabetes. Importantly, genetic deficiency of MasR (MasR-KO) precipitates EPC moblilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes. Three aims are proposed to test the hypothesis. Aim-1 will define the role of MasR in the mobilization and vasoreparative functions of EPCs by using radiation chimeras of MasR-KO mice. Aim-2 will test the beneficial effects of long- term activation of MasR on the development of vasoreparative dysfunction with aging and diabetes. This will be accomplished by overexpressing Ang-(1-7) by adenoviral or nonviral approaches. We will test if the overexpression of Ang-(1-7) will reverse the vasoreparative dysfunction in CD34+EPCs derived from older adults with diabetes. Therefore Aim-2 will provide the proof-of-concept for the translational potential of the study. Aim 3 will demonstrate the involvement of novel pathways that mediate the reversal of mobilization and vasoreparative dysfunctions in diabetic EPCs by MasR activation, Slit/Robo/ROCK pathway and TERT/mitoROS/NO pathway, respectively. Overall, this study will provide a novel mechanism-based pharmacological approach for reversal as well as prevention of diabetic vascular disease in older adults with diabetes.

针对老年人的MAS受体来实现糖尿病血管疾病 抽象的 糖尿病患病率在老年人中很高，预计会升高，糖尿病会增加患的风险 心血管疾病。积累的证据表明，骨髓来源的祖细胞保持 血管健康并促进血管损伤后快速修复。这种先天的血管保护是 由于EPC从骨髓流动到循环的动员而导致衰老和糖尿病减少 并降低了修复受损的血管的能力。因此，可以维护EPC动员的方法 功能将防止糖尿病老年人血管疾病的发展。我们假设 MAS受体是肾素血管紧张素系统血管保护轴的功能介质，赋予 EPC中的动员和修复功能以及对MASR激活的早期干预将 保留先天性血管保护并防止衰老和糖尿病的血管疾病的发展。 该假设是基于我们的新发现，该发现表明血管紧张素转化酶-2产生 MASR的内源性激活剂七肽血管紧张素（ANG） - （1-7）被衰老和 糖尿病。重要的是，MASR（MASR-KO）的遗传缺乏会导致EPC MOBLILOPATHY和 缺血性血管损伤后的血管分析功能障碍，类似于衰老和糖尿病。三个目标是 提议检验该假设。 AIM-1将定义MASR在动员和血管延伸中的作用 通过使用MASR-KO小鼠的辐射嵌合体的EPC功能。 AIM-2将测试长期的有益作用 MASR对衰老和糖尿病的血管延伸功能障碍的发育的术语激活。这会 可以通过通过腺病毒或非病毒方法过表达Ang-（1-7）来实现。我们将测试是否 Ang-（1-7）的过表达将逆转CD34+EPC中的血管分析功能障碍 成人糖尿病。因此，AIM-2将为转化潜力提供概念验证 学习。 AIM 3将证明介导动员逆转的新型途径的参与 通过MASR激活，缝隙/机器/岩石途径和 TERT/MOTOROS/NO途径。总体而言，这项研究将提供基于机制的新型 老年人的逆转和预防糖尿病血管疾病的药理方法 糖尿病。