Assessing and Improving pancreatic islet viability and function

描述(由申请人提供)： 我的实验室的长期目标是通过研究胰岛生理功能障碍来识别和阐明糖尿病和代谢紊乱的机制和原因。糖尿病是一种代谢性疾病，由完全或相对缺乏胰岛素激素引起，目前在美国影响着2080万人，而且发病率正在上升。治疗这种疾病的费用是巨大的，每年超过1350亿美元。越来越多的证据表明，炎症和免疫反应不仅会导致1型糖尿病(T1 DM)患者胰岛中产生胰岛素的β细胞遭到破坏，而且这些因素也会导致2型糖尿病(T2 DM)和其他代谢紊乱患者的β细胞丢失。虽然葡萄糖刺激的胰岛素分泌(GSIS)是衡量胰岛功能的标准指标，但初步数据表明，胰岛功能障碍的一个更敏感的指标是细胞内钙([Ca2]i)，它与胰岛素分泌密切相关。初步数据显示，促炎细胞因子在远低于对胰岛素分泌产生负面影响所需的细胞因子浓度时，会导致胰岛[Ca~(2+)]i处理功能障碍。这一建议的工作模式是，内源性[钙]i振荡的缺陷和葡萄糖刺激的[钙]i变化是胰岛功能和活力受损的早期阶段的指标。基因或药物干预预防或逆转糖尿病的益处将通过[Ca~(2+)]i测量来预测。这项建议的目的是开发更灵敏和准确的胰岛健康评估方法(AIM1)，确定炎性细胞因子诱导的胰岛功能障碍(AIM2)的机制，并使用新的和标准的方法(AIM3)测试新的抗炎治疗以改善胰岛健康(AIM3)。这项建议的具体目的部分是为了评估人类胰岛移植，然而，拟议的研究将产生更大的影响。对胰岛功能障碍的准确、灵敏和系统的评估将被用于识别胰岛水平的功能障碍的早期指标，并阐明其在诸如T1 DM和T2 DM等疾病中的作用机制，以及在胰岛水平评估糖尿病的潜在治疗方法。此外，钙处理功能障碍的来源(S)也将作为胰岛损伤的可能机制(S)进行调查；主要是内质网应激、糖酵解中断和离子通道将结合生理、分子和遗传学方法进行研究。

DESCRIPTION (provided by applicant): The long-term goal of my lab is to identify and elucidate the mechanisms and causes of diabetes and metabolic disorders by investigating dysfunctions in islet physiology. Diabetes mellitus is a metabolic disease that results from either a complete or relative deficiency of the hormone insulin and currently affects 20.8 million people in the U.S. and is increasing in incidence. The cost of caring for this disease is enormous, exceeding 135 billion dollars annually. Increasing evidence suggests that inflammation and immune responses lead to the destruction of insulin-producing beta-cells in pancreatic islets not only in type 1 diabetes (T1DM), but that these factors also contribute to beta-cell loss in type 2 diabetes (T2DM) and other metabolic disorders. Although glucose-stimulated insulin secretion (GSIS) is the standard measure of islet function, preliminary data suggest a more sensitive indicator of islet dysfunction is intracellular calcium ([Ca2+]i), which is closely linked with insulin secretion. Preliminary data show that pro-inflammatory cytokines induce dysfunction in islet [Ca2+]i handling at much lower cytokine concentrations than required to negatively impact insulin secretion. The working model of this proposal is that deficiencies in endogenous [Ca2+]i oscillations and glucose-stimulated changes in [Ca2+]i are indicators of early stages of damage to islet function and viability. Benefits of genetic or pharmacologic interventions to prevent or reverse diabetes will be predicted by [Ca2+]i measurements. The aims of this proposal are to develop more sensitive and accurate methods of assessing islet health (aim1), determine mechanisms of inflammatory cytokine-induced islet dysfunction (aim2), and test novel anti-inflammatory treatments to improve islet health using both novel and standard methods (aim3). The specific aims of this proposal are designed, in part, to evaluate human islets for transplantation, however, the proposed studies will have far greater impact. Accurate, sensitive, and systematic evaluations of islet dysfunction will be used to identify early indicators of dysfunction at the islet level and to elucidate their mechanism in diseases such as T1DM and T2DM, as well as to assess potential therapies for diabetes at the islet level. In addition, the source(s) of dysfunctional calcium handling will also be investigated as a possible mechanism(s) of islet damage; chiefly ER-stress, glycolytic disruption, and ion channels will be examined using a combination of physiological, molecular, and genetic approaches.