INHIBITION OF ADENYLYL CYCLASE TYPE 5: HEALTHFUL AGING PROTECTION

抑制 5 型腺苷酸环化酶：健康的抗衰老保护

• 批准号: 9321949
• 负责人: Dorothy Eileen Vatner
• 金额: $ 19.88万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321949
• 关键词: Accident and Emergency department; Adenosine; Adverse effects; Affect; Aging; Applications Grants; Cardiotonic Agents; Chronic; Conscious; Coronary artery; Development; Diabetes Mellitus; Elderly; Exercise; Family suidae; Funding Opportunities; Goals; Gold; Health; Heart Diseases; High Fat Diet; Infarction; Knock-out; Knockout Mice; Longevity; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Obesity; Oral; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Reperfusion Therapy; Research Project Grants; Time; Toxic effect; adenylyl cyclase type V; aging population; base; clinical translation; clinically relevant; coronary artery occlusion; glucose tolerance; improved; inhibitor/antagonist; instrument; insulin tolerance; laboratory development; novel therapeutics; prevent; response

Project Summary: This grant application is in response to a request from the NIA funding opportunity announcement (FOA), which encourages exploratory/developmental research projects to accelerate the pace of development of novel therapeutics involving biologics, pharmacological and non-pharmacological approaches for preventing and treating key health issues affecting the elderly. The current proposal is based on our laboratory's development of the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which is a model for both longevity and healthful aging. The AC5 KO mouse lives a third longer than its wild type (WT). More importantly for clinical translation, the AC5 KO is protected against diabetes, obesity and cardiac disease and also improves exercise performance, all major factors required for healthful aging. It is obvious that clinical translation of this mechanism, AC5 inhibition, would be extremely important for the aging population. Accordingly, the goal of this proposal is to compare the effects of two known AC5 inhibitors, Ara Ade and PMC6, on the parameters of healthful aging noted above that are known to be protected in the AC5 KO mouse. Another key clinically relevant feature of these AC5 inhibitors is that they protect ischemic myocardium and reduce infarct size, even when administered after coronary artery reperfusion. This is key for clinical translation because when patients with myocardial infarction come to the emergency room, the first priority is to reperfuse the occluded coronary artery, leaving no time to administer a drug. Another aim is to develop a new AC5 inhibitor with minimal side effects that can be administered orally.

项目概要： 此资助申请是对NIA资助机会公告（FOA）请求的回应， 鼓励探索性/发展性研究项目，以加快 涉及生物制剂、药理学和非药理学方法的新疗法， 预防和治疗影响老年人的主要健康问题。目前的建议是基于我们的 实验室开发的腺苷酸环化酶5型（AC 5）敲除（KO）小鼠，这是一个模型， 既长寿又健康的老化。AC 5 KO小鼠的寿命比野生型（WT）长三分之一。更 对于临床转化而言，重要的是，AC 5 KO被保护免于糖尿病、肥胖和心脏病， 还可以提高运动能力，所有这些都是健康衰老所需的主要因素。很明显，临床 这种机制的翻译，AC 5抑制，对于老龄化人群将是极其重要的。 因此，本提案的目的是比较两种已知的AC 5抑制剂Ara Ade和 PMC 6，关于上述健康老化参数，这些参数已知在AC 5 KO中受到保护 老鼠.这些AC 5抑制剂的另一个关键临床相关特征是它们保护缺血性心肌 并且即使在冠状动脉再灌注后给药也能减少梗死面积。这是临床的关键 翻译，因为当心肌梗死患者来到急诊室时， 再灌注闭塞的冠状动脉，没有时间给药。另一个目标是开发一个 新的AC 5抑制剂，副作用最小，可以口服。