Adaptations of Human Islets to Insulin Resistance
人类胰岛对胰岛素抵抗的适应
基本信息
- 批准号:7931202
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmyloidArchitectureBeta CellBlood VesselsCell SurvivalCell physiologyCellsClinical ResearchDiabetes MellitusDietEnvironmental Risk FactorExposure toFatty acid glycerol estersFunctional disorderGLUT4 geneGene ExpressionGeneticGlucoseHealthHumanImmunodeficient MouseIn SituIn VitroIndiumInjuryInsulin ResistanceKnock-outKnowledgeLeptinMethodologyModelingMolecularMonitorMorbidity - disease rateNatural regenerationNon-Insulin-Dependent Diabetes MellitusOxidative StressPopulationPredispositionProliferatingResearch PersonnelRodentRodent ModelSourceStressSystemTestingTherapeutic AgentsTransplantationdiabetes mellitus therapyfeedingimprovedin vivoinsightinsulin secretionisletmortalityresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant):
A major element in the pathophysiology of type 2 diabetes is inadequate insulin secretion in response to insulin resistance. Identifying the molecular mechanisms responsible for the impaired human beta cell response to insulin resistance and therapies optimal for islet survival and function has been slowed by both experimental limitations. Most studies of the islet response to insulin resistance have been performed with rodent islets, but human and rodent islets differ substantially in architecture, cell composition, proliferative capacity, susceptibility to injury, and ability to form islet amyloid. Most studies of human beta cells in experiments intended to mimic insulin resistance (in vitro exposure to fat, glucose, oxidative stress, etc.) have been conducted in vitro because there has been a lack of methodology to study human beta cells in situ. Our team of investigators proposes studies to directly address these gaps in our scientific knowledge using new models and approaches to study the response of human islets in response to insulin resistance in vivo by testing two hypotheses: 1) insulin resistance promotes a multi-level response in human islets (changes in gene expression, ER stress, vascularity); and 2) some currently used therapies for type 2 diabetes are advantageous in promoting islet function and survival in the setting of insulin resistance. The studies will utilize new models that allow human islets to be studied after transplantation into immunodeficient mice that have genetic or dietary forms of insulin resistance (GLUT4 knockout, ob/ob mice, and high fat feeding). We propose three aims: 1) Define the molecular, cellular and vascular changes in human beta cells when they are challenged with insulin resistance in vivo. 2) Investigate which current therapies for type 2 diabetes preserve and/or enhance human beta cell function or survival when human islets are challenged with insulin resistance in vivo. 3) Determine if the in vivo changes in human beta cells in response to insulin resistance resolve when the challenge of insulin resistance is removed. By assessing beta cell function, gene expression, function, and survival, these studies should provide insight and understanding into the islet dysfunction of type 2 diabetes and into which therapeutic agents are most effective in improving human islet function and survival.
PUBLIC HEALTH RELEVANCE:
Type 2 diabetes is a major health problem in the VA system (as many as 20% of the VA population are afflicted with diabetes) and thus, diabetes is a major source of morbidity and mortality. Current treatment is inadequate and the proposed studies will improve our understanding of how insulin secretion becomes impaired and what are the optimal therapies for type 2 diabetes.
描述(由申请人提供):
2型糖尿病的病理生理学中的一个主要因素是响应于胰岛素抵抗的胰岛素分泌不足。由于实验的局限性,确定人类β细胞对胰岛素抵抗的反应受损的分子机制以及胰岛存活和功能的最佳治疗方法的工作进展缓慢。大多数关于胰岛对胰岛素抵抗的反应的研究都是用啮齿类动物的胰岛进行的,但是人类和啮齿类动物的胰岛在结构、细胞组成、增殖能力、对损伤的敏感性和形成胰岛淀粉样蛋白的能力方面有很大的不同。大多数人β细胞的实验研究旨在模拟胰岛素抵抗(体外暴露于脂肪、葡萄糖、氧化应激等)。由于缺乏原位研究人β细胞的方法,我们的研究团队提出研究,以直接解决这些差距,在我们的科学知识,使用新的模型和方法,研究人体胰岛的反应,在体内胰岛素抵抗,通过测试两个假设:1)胰岛素抵抗促进多层次的反应,在人类胰岛(基因表达、ER应激、血管分布的变化);和2)目前用于2型糖尿病的一些疗法在促进胰岛功能和在胰岛素抵抗情况下的存活方面是有利的。这些研究将利用新的模型,使人类胰岛移植到具有遗传或饮食形式的胰岛素抵抗的免疫缺陷小鼠(GLUT 4敲除,ob/ob小鼠和高脂肪喂养)后进行研究。我们提出三个目标:1)定义当人β细胞在体内受到胰岛素抵抗攻击时,它们的分子、细胞和血管变化。2)研究当人体胰岛在体内受到胰岛素抵抗的挑战时,目前2型糖尿病的哪些疗法可以保护和/或增强人体β细胞功能或存活。3)确定当胰岛素抵抗挑战消除时,人体β细胞响应胰岛素抵抗的体内变化是否消退。通过评估β细胞功能、基因表达、功能和存活率,这些研究应该提供对2型糖尿病胰岛功能障碍的深入了解和理解,以及哪些治疗药物在改善人类胰岛功能和存活率方面最有效。
公共卫生关系:
2型糖尿病是VA系统中的主要健康问题(多达20%的VA人群患有糖尿病),因此,糖尿病是发病率和死亡率的主要来源。目前的治疗是不够的,拟议的研究将提高我们对胰岛素分泌如何受损以及2型糖尿病的最佳治疗方法的理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ALVIN C POWERS其他文献
ALVIN C POWERS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ALVIN C POWERS', 18)}}的其他基金
相似国自然基金
基于聚金属氧酸盐对Amyloid蛋白的定点化学修饰及其在阿尔茨海默症治疗中的应用
- 批准号:
- 批准年份:2020
- 资助金额:63 万元
- 项目类别:面上项目
基于S1P通路探究Amyloid-β在干性年龄相关性黄斑变性中的作用
- 批准号:81870666
- 批准年份:2018
- 资助金额:57.0 万元
- 项目类别:面上项目
Amyloid-beta-PirB 相互作用介导小胶质细胞表型和功能变化参与AD进展的机制研究
- 批准号:81601123
- 批准年份:2016
- 资助金额:17.0 万元
- 项目类别:青年科学基金项目
Beta-amyloid寡聚体特有的抗原表位多肽疫苗的研究
- 批准号:30971012
- 批准年份:2009
- 资助金额:35.0 万元
- 项目类别:面上项目
抗阿兹海默病Beta-Amyloid寡聚物单链可变区抗体的筛选及其动物试验
- 批准号:30570622
- 批准年份:2005
- 资助金额:30.0 万元
- 项目类别:面上项目
相似海外基金
Elucidating the function of a protective protein in a novel in vitro reconstitution system for disaggregation of ubiquitinated amyloid fibrils
阐明保护蛋白在新型体外重构系统中用于解聚泛素化淀粉样蛋白原纤维的功能
- 批准号:
24K10522 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
新規amyloid-β抑制因子ILEIの減少に伴うアルツハイマー病リスクと分子制御機構の解析
新型β淀粉样蛋白抑制剂ILEI降低相关阿尔茨海默病风险及分子调控机制分析
- 批准号:
23K06805 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Extracting the detrimental effects of amyloid beta oligomer using contextual learning and controlling it with antagonist molecules
使用情境学习提取β淀粉样蛋白寡聚体的有害影响并用拮抗剂分子控制它
- 批准号:
23K06348 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Project 3: 3-D Molecular Atlas of cerebral amyloid angiopathy in the aging brain with and without co-pathology
项目 3:有或没有共同病理的衰老大脑中脑淀粉样血管病的 3-D 分子图谱
- 批准号:
10555899 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Development of inhibitors for amyloid peptide aggregation based on peptidomimetics
基于拟肽的淀粉样肽聚集抑制剂的开发
- 批准号:
23K14318 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effect of abnormal beta-amyloid on Ca dynamics in neural cells
异常β-淀粉样蛋白对神经细胞钙动力学的影响
- 批准号:
23K14744 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of novel functions of presenilin in ApoE secretion and brain amyloid removal
阐明早老素在 ApoE 分泌和脑淀粉样蛋白去除中的新功能
- 批准号:
23KF0156 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for JSPS Fellows
Mechanisms underlying Sex differences in Cerebral Amyloid Angiopathy: The Fibrin-Microglia Crosstalk
脑淀粉样血管病性别差异的潜在机制:纤维蛋白-小胶质细胞串扰
- 批准号:
10662862 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Probing Amyloid Fibril Self-Assembly with Network Hamiltonian Simulations in Explicit Space
用显式空间中的网络哈密顿模拟探测淀粉样蛋白原纤维的自组装
- 批准号:
10715891 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Astrocytic exocytosis of ATP in amyloid pathology and Alzheimer's disease
淀粉样蛋白病理学和阿尔茨海默病中 ATP 的星形细胞胞吐作用
- 批准号:
10722422 - 财政年份:2023
- 资助金额:
-- - 项目类别: