Assessing and Improving pancreatic islet viability and function

评估和改善胰岛活力和功能

• 批准号: 7667333
• 负责人: Craig S Nunemaker
• 金额: $ 10.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667333
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Beta Cell; Biological Assay; Calcium; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Classification; Data; Diabetes Mellitus; Disease; Dose; Effectiveness; Evaluation; Functional disorder; Gene Expression; Genetic; Glucose; Glucose tolerance test; Goals; Health; Histology; Human; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Ion Channel; Islets of Langerhans; Islets of Langerhans Transplantation; Lead; Life; Link; Magnetic Resonance Imaging; Measurement; Measures; Metabolic Diseases; Methods; Modeling; Molecular Genetics; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxygen Consumption; Physiological; Physiology; Relative (related person); Small Interfering RNA; Source; Staging; Streptozocin; Stress; System; Testing; Transplantation; Work; base; cost; cytokine; design; diabetes mellitus therapy; fluorescence imaging; hormone deficiency; improved; in vivo; insulin secretion; islet; killings; novel; prevent; standard measure

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.

描述（由申请人提供）： 我实验室的长期目标是通过研究胰岛生理功能障碍来确定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，由激素胰岛素的完全或相对缺乏引起，目前在美国影响2080万人，并且发病率正在增加。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导致1型糖尿病（T1 DM）胰岛中产生胰岛素的β细胞的破坏，而且这些因素也导致2型糖尿病（T2 DM）和其他代谢紊乱中的β细胞损失。尽管葡萄糖刺激的胰岛素分泌（GSIS）是胰岛功能的标准测量，但初步数据表明胰岛功能障碍的更敏感指标是细胞内钙（[Ca 2 +]i），其与胰岛素分泌密切相关。初步数据显示，促炎细胞因子在比负面影响胰岛素分泌所需的细胞因子浓度低得多的细胞因子浓度下诱导胰岛[Ca 2 +]i处理功能障碍。该建议的工作模型是内源性[Ca 2 +]i振荡和葡萄糖刺激的[Ca 2 +]i变化的缺陷是胰岛功能和活力受损的早期阶段的指标。遗传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。该提案的目的是开发更敏感和准确的方法来评估胰岛健康（aim 1），确定炎症性胰岛功能障碍的机制（aim 2），并测试新的抗炎治疗，以改善胰岛健康使用新的和标准的方法（aim 3）。该提案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、敏感和系统性评价将用于确定胰岛水平功能障碍的早期指标，并阐明其在T1 DM和T2 DM等疾病中的机制，以及评估胰岛水平糖尿病的潜在治疗方法。此外，还将研究功能障碍性钙处理的来源作为胰岛损伤的可能机制;主要是ER应激、糖酵解破坏和离子通道将使用生理学、分子学和遗传学方法的组合进行检查。