Glycation and mu dicarbonyls in diabetic complications

描述(申请人提供)：我的目标是将我在糖尿病并发症的生化基础方面的专业知识与我的临床研究结合起来，开发新的方法来理解这一毁灭性疾病的发病机制。我的职业生涯经历了几个阶段，包括基础科学、临床内分泌学家和教育家，但在过去的10年里，我完全致力于继续发展强大的临床研究项目。我相信，对于那些考虑从事临床研究的人来说，这样的项目可以成为一个榜样。正在通过K-24计划寻求资金，以继续这一过渡，并实现受保护的时间块，以便专注于我的研究，并为临床研究人员的培训制定指导计划。从长远来看，我的目标是创建一个稳定和富有成效的研究计划，跨越临床和基础科学之间迄今被忽视的差距，并为新的研究人员提供肥沃的培训场地。研究和指导将在达特茅斯医学院(DMS)及其两个主要临床设施-达特茅斯-希区柯克医疗中心(DHMC)和怀特河联合退伍军人医院(VAH)进行。该机构为寻找受过良好教育和积极进取的实习生提供了丰富的环境，并拥有临床研究计划所需的所有设施。我已经精心准备了一个全面的指导计划，如果这个奖项被授予，就可以立即实施。该计划旨在使受训人员熟练地规划、执行和完成研究项目，这些项目提供了一个将强大的分析工具与精心挑选的临床人群相结合的模型，以解决与糖尿病相关的重要问题。 在5年的授权期内，我建议将我的时间花在三个同时进行的项目上，评估非酶糖基化、二羰基和AGEs在糖尿病并发症发病机制中的作用。目前正在进行或计划中的项目包括。A.结合剂对α-二羰基的产生、解毒和清除以及糖尿病大血管并发症进展的作用和机制，b.餐后高血糖对α-二羰基、组织糖基化和糖尿病大血管并发症的作用。C.甲基乙二醛的产生和果糖胺3激酶(FN3K)脱糖在控制葡萄糖介导的非酶糖化和糖尿病肾病易感性中的作用。更多的临床项目将作为选定的基础研究项目在我的实验室中“成熟”，并随着其他研究群体提出改进的模型来测试我们的假设。这些令人兴奋的研究项目，以及即将出现的新项目，与拟议的指导/培训计划相结合，提供了吸引和奖励新一代临床研究人员的真正机会。

DESCRIPTION (provided by applicant): My objective is to combine my expertise in the biochemical basis of diabetic complications with my clinical research to develop new approaches for understanding the pathogenesis of this devastating cluster of diseases. My career has had several phases, including basic science, clinical endocrinologist, and educator, but over the past 10 years I have become fully committed to the continued development of a strong clinical research program. I believe that such a program could be a model for those considering a career in clinical investigation. Funding is being sought through this K-24 program to continue this transition and achieve blocks of protected time to focus on my research and develop a mentoring program for the training of clinical investigators. Over the longer term, my objectives are to create a stable and productive research program which will span the hitherto neglected gap between clinical and basic science and provide a fertile training ground for new investigators. The research and mentoring will take place at Dartmouth Medical School (DMS) and its two major clinical facilities, the Dartmouth-Hitchcock Medical Center (DHMC) and the White River Junction Veterans Hospital (VAH). This institution offers a rich milieu for one seeking well educated and highly motivated trainees, and has all of the required facilities for clinical research program. I have carefully prepared a comprehensive mentoring program which can be immediately implemented if this award is granted. This program is designed to give the trainees proficiency in the planning, execution and completion of study projects that provide a model combining powerful analytical tools with carefully selected clinical populations to solve important diabetes related questions. Over the 5 years of the granting period I propose to spend my time on three concurrent projects evaluating the role of nonenzymatic glycation, dicarbonyls, and AGEs in the pathogenesis of diabetic complications. The projects currently in progress or planned include. a. Effect and mechanism of action of binding agents on the production, detoxification, and scavenging of alpha-dicarbonyls and the progression of diabetic macrovascular complications, b. The role of post-prandial hyperglycemia on alpha-dicarbonyls, tissue glycation, and diabetic macrovascular complications. c. Methylglyoxal production and the role of Fructosamine 3 Kinase (FN3K) deglycation in the control of glucose-mediated nonenzymatic glycation and predisposition to diabetic nephropathy . Additional clinical projects will be added as selected basic research projects in my laboratory "mature" and as other study populations present improved models to test our hypotheses. These exciting research projects, and new ones on the horizon, combined with the proposed mentoring/training program offers real opportunities of attracting and rewarding a new generation of clinical investigators.