Molecular mechanisms underlying NHP pancreatic beta cell failure, and recovery

描述（由申请人提供）：我们的研究团队经验丰富，富有成效，拥有互补的技能，资源和技术来解决所有糖尿病共同的基本问题：“为什么胰腺β细胞衰竭？”具体来说，我们将利用我们三个合作机构（俄勒冈国家灵长类动物研究中心，范德比尔特大学和马萨诸塞大学）开发的独特优势，使用健康供体和各种特定代谢紊乱状态的供体，全面表征非人类灵长类动物（NHP）胰岛的细胞组成，功能和基因表达谱。此外，现在有可能第一次，我们将确定个体胰岛亚群的基因表达谱，使用健康和代谢紊乱的供体灵长类动物，这些动物已经仔细表型化。虽然最终目标是阐明人类胰岛的结构和功能，但相对于从人类和啮齿动物供体中分离的胰岛，NHP模型供体特别适合这些研究，即：(1)虽然啮齿动物的胰岛在结构和功能方面与人类的胰岛有很大不同，但NHP和人类的胰岛似乎非常相似。(2)人体胰岛完全是从尸体供体中分离出来的，因此无法评估供体先前的代谢状态。随着时间的推移，NHP供体反复出现代谢表型。(3)人的胰腺受到不同时期的热缺血和冷缺血的影响，从而影响胰岛的活力、功能和基因表达。NHP胰腺是在最小冷缺血的受控条件下从手术麻醉的供体中获得的。我们团队的研究和未来的工作将从我们的合作中成长起来，这将使我们能够确定标志胰腺β细胞不健康的新参数，以及与胰岛在功能障碍期后显示改善功能相关的新生物标志物。这些标记物可以作为潜在的治疗靶点，以预防或应对导致1型和2型糖尿病的β细胞衰竭。

DESCRIPTION (provided by applicant): Our team of experienced and productive investigators has the complementary skills, resources, and technologies to address the fundamental problem common to all diabetes: "Why do pancreatic beta cells fail?" Specifically, we will utilize the unique strengths developed at our three collaborating institutions (Oregon National Primate Research Center, Vanderbilt University, and the University of Massachusetts) to fully characterize non-human primate (NHP) islets' cellular composition, function, and gene expression profiles, using healthy donors, and donors in various specific metabolically perturbed states. In addition, and now possible for the first time, we will determine individual islet subsets' gene expression profiles using both healthy and metabolically challenged donor primates after those animals have been carefully phenotyped. While the ultimate goal is to elucidate human islet structure and function, relative to islets isolated from human and rodent donors, NHP model donors are distinctively well suited for these studies, i.e.: (1) While rodent islets differ significantly from human islets with regard to structure and function, NHP and human islets appear to be quite similar. (2) Human islets are exclusively isolated from cadaveric donors and as such the donor's pre-existing metabolic state cannot be assessed. The NHP donors are repeatedly metabolically phenotyped over time. (3) Human pancreases are subjected to variable periods of both warm- and cold-ischemia which affect islet viability, function, and gene expression. NHP pancreata are procured from surgically anesthetized donors under controlled conditions with minimal cold ischemia. Our team's studies and future work that will grow from our collaboration will enable us to identify new parameters that mark pancreatic beta cells as unhealthy, as well as novel biomarkers associated with islets displaying improved function after periods of dysfunction. Such markers can serve as potential therapeutic targets to prevent or respond to the beta cell failure that underlies both type-1 and type-2 diabetes. PUBLIC HEALTH RELEVANCE: A detailed characterization of beta cell biology will promote the rational design of therapies to abrogate the loss in pancreatic beta cell function that underlies diabetes and/or promote beta cell function recovery as occurs in many patients following bariatric surgery. Our team's efforts will utilize the relevant NHP model.