BLRD Research Career Scientist Award Application

糖尿病是一种严重的疾病，由胰岛素作用失败和/或胰岛素不足引起。 胰腺β细胞的分泌物。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提供的医疗保健。因此，努力理解 这种衰弱疾病的病理生理学与护理和治疗的未来发展高度相关 这种疾病的治疗学。PI从事糖尿病研究已有近30年的历史。他的 目前的研究目的是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。他的实验室做出的开创性贡献 明确了小G蛋白Rac1在胰岛β细胞功能障碍发病机制中的新作用 代谢应激和糖尿病状况。他目前的研究是基于这样一个假设： 代谢应激促进rac1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/崩溃导致功能性β细胞丧失 质量。他的团队还致力于确定rac1激活过程中的关键信号蛋白/因素- 可能导致胰腺β细胞代谢和功能缺陷的失活周期。 这些研究运用了最先进的显微、分子生物学、蛋白质组学和脂类组学。 涉及胰岛素分泌受损动物模型的胰岛和胰岛的入路 来自T2D人类捐赠者。 除了他正在进行的调查(如上)外，在下一次延期期间，私家侦探将继续 合作研究开发新型小分子和基于多肽的抑制剂 在体外和体内代谢应激模型和体内模型中阻止胰岛β-细胞的代谢缺陷 糖尿病。PI和他的合作者在这一领域的长期专业知识将提供独特的 有机会解决胰岛功能在健康和糖尿病方面的这些重要方面。此外， PI将继续他正在进行的、高效的、合作的研究，以破译分子和 细胞机制参与糖尿病视网膜病变的发病机制。最后，公安部建议： 与JDD VAMC的研究人员建立新的合作关系，以评估胰岛β细胞功能 创伤性脑损伤和创伤后应激障碍的动物模型。在这一领域存在重大的知识差距，这是非常严重的 与退伍军人管理局的医疗保健任务有关。总的来说，从这些互补性中积累数据 调查将提供对糖尿病预防和治疗产生影响的可操作的见解 以及与之相关的人类并发症，包括退伍军人。 为支持拟议的调查，国际刑警组织已经建立了许多合作 与退伍军人事务部和非退伍军人事务部的调查人员在一起。他的工作效率很高，出版了大量的高级出版物 影响期刊；其中大部分是他的实习生和合作者合著的。他写道 在包括内分泌评论、糖尿病、 肥胖与新陈代谢和综合生理学。总而言之，此应用程序寻求续订 科卢鲁博士的一项成熟和高度认可的SRCS计划，用于研究 糖尿病及其相关并发症的病理生理学，这是我们的高度优先计划 弗吉尼亚医疗保健系统。

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.