BLRD Research Career Scientist Award Application

糖尿病是一种严重的医学疾病，由胰岛素作用失败和/或胰岛素不足引起 从胰腺β细胞分泌。糖尿病影响了大约20%的退伍军人， 通过退伍军人健康管理局的医疗保健。因此，努力了解 这种使人衰弱的疾病的病理生理学与未来的护理发展高度相关， 治疗这种疾病。PI已经进行了近30年的糖尿病研究。他 目前的研究旨在了解潜在的分子和细胞机制， β细胞功能障碍导致糖尿病的发病。他的实验室的种子贡献 Rac 1是一种小G蛋白，在胰岛β细胞功能障碍的发病机制中， 代谢应激和糖尿病状况。他目前的研究是基于这样的假设， 代谢应激促进Rac 1的功能和转录激活，以促进细胞内 氧化应激、线粒体和核损伤/塌陷导致功能性β细胞丧失 马萨诸塞州他的团队还旨在确定Rac 1激活中的关键信号蛋白/因子- 这可能导致胰腺β细胞中的代谢和功能缺陷。 这些研究采用了最先进的显微镜、分子生物学、蛋白质组学和脂质组学 涉及源自胰岛素分泌受损的动物模型的胰岛以及胰岛的方法 2型糖尿病患者的捐赠者 除了正在进行的研究（如上所述）外，在下一个续约期内，PI将继续 合作研究，以开发新的小分子和肽为基础的抑制剂， 在代谢应激的体外和体内模型中停止胰岛β细胞的代谢缺陷， 糖尿病PI及其合作者在该领域的长期专业知识将提供独特的 有机会解决健康和糖尿病中胰岛功能的这些重要方面。此外，委员会认为， PI将继续进行他正在进行的，高生产力的，合作研究，以破译分子和 糖尿病视网膜病变的发病机制。最后，PI建议 与JDD VAMC的研究人员建立新的合作，以评估胰岛β细胞功能， TBI和PTSD的动物模型。在这一领域存在着重大的知识差距， 与退伍军人事务部的医疗使命有关。总的来说，数据来自这些互补的 调查将提供可操作的见解，这将影响糖尿病的预防和治疗 及其在人类中的相关并发症，包括我们的退伍军人。 为了支持拟议的调查，PI已经建立了许多合作关系 与退伍军人事务部和非退伍军人事务部的调查员他的工作效率很高，在高等教育领域发表了大量的论文。 影响力期刊;其中大部分是由他的学员和合作者共同撰写的。他写道 权威评论这些主题的领先期刊，包括内分泌评论，糖尿病， 肥胖和代谢，以及综合生理学。总之，本申请寻求更新 Kowluru博士的一个完善且高度认可的SRCS项目，用于研究 糖尿病及其相关并发症的病理生理学，这是我们的一个高优先级项目， 卫生保健系统。

Diabetes is a serious medical condition resulting from failure of insulin action and/or insufficient insulin secretion from the pancreatic β-cells. Diabetes affects approximately 20% of the Veterans that receive health care through the Veterans Health Administration. Therefore, efforts to understand the pathophysiology of this debilitating disease are highly relevant to future developments in care and therapeutics of this disease. The PI has been conducting diabetes research for nearly 30 years. His current investigations are aimed at understanding the molecular and cellular mechanisms underlying β-cell dysfunction leading to the onset of diabetes. Seminal contributions from his laboratory have defined novel roles for Rac1, a small G-protein, in the pathogenesis of islet β-cell dysfunction under metabolic stress and diabetic conditions. His current studies are based on the hypothesis that metabolic stress promotes functional and transcriptional activation of Rac1 to promote intracellular oxidative stress, mitochondrial and nuclear damage/ collapse leading to the loss of functional β-cell mass. His team is also aiming to identify key signaling proteins/factors in the Rac1 activation- deactivation cycle that might contribute to the metabolic and functional defects in the pancreatic β-cell. These studies employ state-of-the art microscopic, molecular biological, proteomics and lipidomics approaches involving islets derived from animal models of impaired insulin secretion as well as islets from T2D human donors. In addition to his ongoing investigations (above), during the next renewal period, the PI will continue collaborative studies toward the development of novel small molecule and peptide-based inhibitors for halting metabolic defects of the islet β-cell in in vitro and in vivo models of metabolic stress and diabetes. The long-standing expertise of the PI and his collaborators in this field will provide a unique opportunity to address these important aspects of islet function in health and diabetes. Furthermore, the PI will continue his ongoing, highly productive, collaborative studies to decipher the molecular and cellular mechanisms involved in the pathogenesis of diabetic retinopathy. Lastly, the PI proposes to establish new collaborations with researchers at the JDD VAMC to assess islet β-cell function in animal models of TBI and PTSD. Significant knowledge gaps exist in this area, which is highly relevant to the VA healthcare mission. Collectively, data accrued from these complementary investigations will provide actionable insights that will impact the prevention and treatment of diabetes and its associated complications in humans, including our Veterans. In support of the proposed investigations, the PI has already established numerous collaborations with VA and non-VA investigators. He is highly productive with a large number of publications in high impact journals; the majority of which are coauthored by his trainees and collaborators. He wrote authoritative reviews on these topics in leading journals including Endocrine Reviews, Diabetes, Obesity and Metabolism, and Comprehensive Physiology. In summary, this application seeks renewal of Dr. Kowluru’s a well-established and highly recognized SRCS program for studies on pathophysiology of diabetes and its associated complications, which is a high priority program for our VA healthcare system.