A Stress-Induced Vicious Cycle In The Development of T1D

压力诱发 T1D 发展的恶性循环

基本信息

批准号：
10653099
负责人：
PETER ARVAN
金额：
$ 70.36万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653099
关键词：
ATF6 gene Acceleration Address Affect American Apoptosis Applications Grants Autoimmunity Automobile Driving Beta Cell Biochemical Biological Assay C-Peptide Calcium Cell Death Cell Survival Cell physiology Collaborations Coupled Data Defect Development Diabetes Mellitus Disease Disparate EIF-2alpha Endoplasmic Reticulum Environmental Risk Factor Enzymes Event Failure Functional disorder Future Generations Genetic Homeostasis Human ITPR1 gene Immune system Impairment In Vitro Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intention Islets of Langerhans Laboratories Link Measurement Mediating Membrane Membrane Proteins Metabolism Mitochondria Modeling Nature Neurodegenerative Disorders Optical reporter Pancreas Pathway interactions Patients Peptide Signal Sequences Peptides Phase Phosphorylation Predisposing Factor Predisposition Process Proinsulin Proteins Request for Applications Respiration Role Signal Transduction Site Stimulus Stress Stress Response Signaling Structure of beta Cell of islet Testing Transplantation Ubiquitin Variant Western Blotting Work Xenograft Model autoimmune pathogenesis biological adaptation to stress blood glucose regulation cell injury cytokine effector T cell endocrine pancreas development endoplasmic reticulum stress genetic approach in vivo in vivo Model insulin dependent diabetes mellitus onset insulin secretion islet islet xenograft mitochondrial metabolism neoantigens novel pharmacologic preproinsulin preservation prevent protein folding response stress kinase therapeutically effective translation factor trigger point ubiquitin ligase ubiquitin-protein ligase

项目摘要

A VICIOUS CYCLE OF (PRE)PROINSULIN-MEDIATED ER STRESS, UBIQUITIN-LIGASE ACTIVATION, and DISORDERED Ca2+-HANDLING IN PANCREATIC BETA CELLS This proposal is submitted in response to a request-for-applications for Discovery of Early Type 1 Diabetes Disease Processes in the Human Pancreas (including the possibility of studies of signaling/processing pathways that are dysregulated in stressed beta cells during the asymptomatic phase of T1D). Our group of three pancreatic beta cell biologists with distinct expertise (Drs. Arvan, Soleimanpour, and Satin) brings forward a novel hypothesis about the initiating beta cell events in T1D, with the realization that these intricacies exceed what any one laboratory could exhaustively study on their own. Specifically, the three collaborating P.I.s propose a chain of beta cell defects that can be initiated and exacerbated by pro- inflammatory stimuli but are then further propagated by a failure of inter-organellar support, including the endoplasmic reticulum (ER) and mitochondria. It is well known that activation of ER stress signaling upon perturbation of ER homeostasis (launched from multiple potential initiators, including proinflammatory cytokines) triggers activation of stress kinases that include (but are not limited to) the ER membrane protein, PERK. New evidence suggests that ER stress kinase activity results in phosphorylation (and thereby activation) of one or more E3 ubiquitin (Ub) ligases residing at ER-mitochondrial contact sites known as MAMs. We posit that ER stress-related E3 Ub-ligase activation stimulates ubiquitylation and proteasomal turnover of a number of MAM resident proteins including the well-recognized mitochondrial substrate, mitofusin-2, but also key components of ER-to-mitochondrial Ca2+ transfer including IP3R1 and others. ER stress-provoked degradation of MAM protein components can be evaluated biochemically and quantitatively by Western blotting; but we go beyond this to examine the functional consequences via measurements of impaired ER-to- mitochondrial Ca2+ transfer. We propose that such calcium imbalance further impairs mitochondrial function including (but not limited to) impaired ATP generation, which exacerbates the perturbation of ER homeostasis with concomitant ER stress. In short, we propose that pro-inflammatory triggers of T1D can initiate a vicious cycle leading to beta cell failure. This hypothesis will be tested in human islets in vitro as well as in an in vivo model involving transplanted human islets. Finally, we propose to probe certain trigger points to break the vicious cycle, in an attempt to rescue beta cell survival and function, with the intention of preventing T1D onset and progression. 1

（前）促硫素介导的ER应激，泛素 - 岩酶激活的恶性循环，和胰腺β细胞中的Ca2+无序疗法该提案是根据发现早期1型糖尿病的申请提交的提交人胰腺中的疾病过程（包括进行信号/加工研究的可能性在T1D的无症状阶段，在应力β细胞中失调的途径。我们的由三个具有独特专业知识的胰腺β细胞生物学家组成的小组（Arvan博士，Soleimanpour和缎面提出了一个关于T1D中启动β细胞事件的新假设，并意识到这些复杂性超出了任何一个实验室可以自行研究的东西。具体来说，这三个合作的P.I.提出了一系列Beta细胞缺陷链炎症性刺激，但随后通过跨加工支撑的失败进一步传播内质网（ER）和线粒体。众所周知，ER应力信号在 ER稳态的扰动（由多个潜在的发起人推出，包括促炎细胞因子）触发应激激酶的激活，包括（但不限于）ER膜蛋白，振作。新证据表明，ER应力激酶活性会导致磷酸化（从而一个或多个E3泛素（UB）连接酶的激活），该连接酶位于er-Mitochrial接触位点，称为MAM。我们认为与ER应力相关的E3 UB - 连接酶激活刺激了A的泛素化和蛋白酶体更新 MAM驻留蛋白数量，包括公认的线粒体底物丝线Fusin-2，还包括 ER到线粒体Ca2+转移的关键组成部分，包括IP3R1等。 ER发动压力 MAM蛋白成分的降解可以通过西方对生化和定量评估斑点但是，我们超越了这一点，通过测量受损的ER到 - 线粒体Ca2+转移。我们建议这种钙不平衡进一步损害线粒体功能包括（但不限于）ATP生成受损，这加剧了ER稳态的扰动与伴随的ER应力。简而言之，我们建议T1D的促炎性触发器可以启动恶性循环导致β细胞衰竭。该假设将在人类的体外和人类胰岛中进行检验一个涉及移植人类胰岛的体内模型。最后，我们建议探测某些触发点打破恶性循环，试图挽救Beta细胞的存活和功能，以防止 T1D发作和进展。 1