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.

项目摘要： 该赠款申请是响应NIA资助机会公告（FOA）的请求， 这鼓励探索性/发展研究项目加速 涉及生物制剂，药理学和非药理学方法的新型治疗剂 防止和治疗影响老年人的关键健康问题。当前的提议是基于我们的 实验室的腺苷酸环化酶5型（AC5）敲除（KO）小鼠的发展，这是一个模型 寿命和健康衰老。 AC5 KO鼠标的寿命比其野生型（WT）长三分之一。更多的 重要的是，对于临床翻译，AC5 KO受到保护免受糖尿病，肥胖和心脏疾病的保护，以及 还可以改善运动表现，这是健康衰老所需的所有主要因素。很明显临床 这种机制的翻译AC5抑制作用对于老龄化人群非常重要。 因此，该提案的目的是比较两个已知的AC5抑制剂ARA ADE和 PMC6，关于已知在AC5 KO中受到保护的健康衰老的参数 老鼠。这些AC5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 并降低梗塞大小，即使在冠状动脉再灌注后进行给药。这是临床的关键 翻译是因为当心肌梗塞的患者来到急诊室时，首要任务是 为了代替封闭的冠状动脉，没有时间给药。另一个目的是开发 新的AC5抑制剂具有最小的副作用，可以口服。