Molecular mechanisms underlying NHP pancreatic beta cell failure, and recovery

描述(由申请人提供)：我们的经验丰富且富有成效的研究团队拥有互补的技能、资源和技术来解决所有糖尿病共同的根本问题：“为什么胰岛β细胞会失效？”具体地说，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，利用健康的捐赠者和处于各种特定代谢紊乱状态的捐赠者，全面描述非人类灵长类(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，我们将使用健康的和代谢困难的供体灵长类动物在仔细进行表型鉴定后确定单个胰岛亚群的基因表达谱。虽然最终目的是阐明人类胰岛的结构和功能，但相对于分离自人和啮齿动物供体的胰岛，NHP模型供体非常适合于这些研究，即：(1)虽然啮齿动物胰岛在结构和功能上与人类胰岛有显著差异，但NHP和人类胰岛似乎非常相似。(2)人类胰岛完全从身体捐赠者身上分离出来，因此无法评估捐赠者先前存在的代谢状态。随着时间的推移，NHP捐赠者的新陈代谢表型会反复出现。(3)人胰腺处于不同的冷热缺血期，影响胰岛的存活率、功能和基因表达。NHP胰腺取自手术麻醉的供体，在受控条件下进行最小程度的冷缺血。我们团队的研究和未来的工作将在我们的合作中发展，这将使我们能够识别标记胰腺β细胞为不健康的新参数，以及与胰岛在功能障碍时期后表现出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。 公共卫生相关性：β细胞生物学的详细特征将促进合理的治疗设计，以消除导致糖尿病的胰岛β细胞功能丧失和/或促进β细胞功能恢复，就像许多减肥手术后发生的那样。我们团队的努力将利用相关的NHP模式。

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.