Secretory Pathway Protein Degradation Maintains Insulin Biogenesis + Secretion

分泌途径蛋白质降解维持胰岛素生物合成分泌

基本信息

批准号：
10217112
负责人：
PETER ARVAN
金额：
$ 63.69万
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：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10217112
关键词：
Anabolism Animals Area Autophagocytosis Bacteriophages Belief Beta Cell Biogenesis Biological Blood Glucose Cell physiology Cells Complex Coupled Data Defect Degradation Pathway Development Diabetes Mellitus Disease Disease Progression Distal Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Ensure Failure Functional disorder Genes Genetic Glucose Golgi Apparatus Grant Homeostasis Hormones Human Hyperactivity INS gene Insulin Insulin deficiency Knockout Mice Lead Link Lysosomes Maintenance Membrane Messenger RNA Mind Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Peptide Signal Sequences Phenotype Predisposition Process Production Proinsulin Proteins Qi Quality Control Research Research Personnel Role Route Secretory Cell Secretory Vesicles Site Structure of beta Cell of islet TGF Beta Signaling Pathway Therapeutic Translations Vesicle Work Youth anterograde transport base biological adaptation to stress dalton diabetes pathogenesis diabetes risk endoplasmic reticulum stress follow-up islet mutant non-diabetic novel therapeutic intervention preproinsulin prevent protein degradation recruit risk variant secretory protein signal sequence receptor success transcription factor transcriptomics

项目摘要

Pancreatic beta-cells synthesize large quantities of insulin. Growing evidence indicates that any of a number of deficiencies in insulin biosynthesis (genetic, or acquired) can lead to diabetes. We know that insulin biosynthesis begins with translation of preproinsulin. This short-lived precursor must be translocated into the endoplasmic reticulum (ER), signal peptide excised, and proinsulin properly folded in order to undergo successful export from the ER for delivery to the distal secretory pathway in which proinsulin-to-insulin processing and insulin storage in secretory granules finally occurs. In contrast, unsuccessful molecules may be degraded before they are even translocated into the ER, or may be restrained from anterograde export from the ER — indeed, strong evidence indicates that misfolded proinsulin molecules are targeted for degradation. Secretory pathway protein degradation also involves other endogenous substrates that contribute to the differentiated pancreatic beta cell phenotype. The competing continuation of this multi-P.I. R01 will help clarify how three major mechanisms of secretory pathway protein disposal – pre-translocation degradation; ER-Associated Degradation (ERAD); and Autophagy – are all critical for proper beta-cell function. This proposal continues the longstanding association of three tightly collaborative investigators (Qi, Tsai, Arvan) that are experts in exactly these processes: preproinsulin translocation into the ER lumen with the subsequent folding/misfolding of proinsulin, secretory pathway protein degradation via ERAD, and an ER-to-lysosome degradative pathway that we believe is primarily ER-autophagy (ER-phagy). We have strong reason to believe that defects in these quality control mechanisms are linked to type 2 diabetes (T2D) as a result of insulin insufficiency, and this belief is supported by preliminary data. In this proposal, we seek to examine three interlinked areas related to the early secretory pathway of pancreatic beta-cells. For one, we will pursue studies in which infidelity of preproinsulin translocation across the ER membrane is directly linked to deficient proinsulin and insulin biosynthesis, leading directly to diabetes. Second, we will follow-up on some remarkable preliminary data demonstrating that de-differentiation of pancreatic beta-cells is triggered by a loss of efficient ERAD function, also leading directly to insulin-deficient diabetes. Finally, we not only delve deeply into the ER factors that trigger ER-phagic degradation of misfolded proinsulin, but we also propose a deeper understanding of how ineffective or improper ER-phagy can trigger beta cell failure, which also leads directly to insulin-deficient diabetes. These new research directions lead us to pursue a novel therapeutic approach to beta-cell secretory pathway dysfunction focused on stimulating intracellular protein clearance mechanisms, in order to prevent diabetes onset and/or limit its progression.

胰腺β细胞合成大量胰岛素。越来越多的证据表明，胰岛素生物合成（遗传或获得）的许多缺陷都可以导致糖尿病。我们知道，胰岛素生物合成始于前胰岛素的翻译。该短寿命的前体必须被翻译成内质网（ER），信号肽优异，促二硫酸蛋白蛋白恰当地折叠，以便从ER中成功出口，以传递到远端的秘密途径，在这些途径中，在秘密granuules中，秘密蛋白 - 胰岛素储存和胰岛素存储最终最终发生。相比之下，在将它们转移到ER中之前可能会降解不成功的分子，或者可以从ER的顺行导出中恢复 - 实际上，有力的证据表明，错误折叠的促硫素分子的目标是降解。秘书长途径蛋白降解还涉及其他有助于分化胰腺β细胞表型的内源性底物。此多p.i的竞争延续。 R01将有助于阐明如何处理秘密途径蛋白处理的三种主要机制 - 转换前降解； ER相关的降解（ERAD）；和自噬 - 都是适当的β细胞功能至关重要的。 This proposal continues the longstanding association of three tightly collaborative investigators (Qi, Tsai, Arvan) that are experts in exactly these processes: preproinsulin translocation into the ER lumen with the subsequent folding/misfolding of proinsulin, secret pathway protein degradation via ERAD, and an ER-to-lysosome degradative pathway that we believe is primary ER-autophagy (ER-phagy).我们有强有力的理由相信，这些质量控制机制的缺陷与胰岛素不足的结果与2型糖尿病（T2D）有关，并且这种信念得到了初步数据的支持。在该提案中，我们试图研究与胰腺β细胞早期秘密途径有关的三个相互联系的区域。首先，我们将进行研究，其中跨ER膜的前胰岛素易位性与缺乏胰岛素和胰岛素生物合成直接相关，直接导致糖尿病。其次，我们将跟进一些显着的初步数据，表明胰腺β细胞的脱节是由有效的ERAD功能丧失触发的，这也直接导致胰岛素缺陷型糖尿病。最后，我们不仅深入研究了触发错误折叠蛋白质硫蛋白的ER - 症状降解的ER因子，而且我们还提出了对无效或不当ER-PHAGY如何触发β细胞衰竭的更深入的了解，这也直接导致胰岛素缺乏症缺乏症状糖尿病。这些新的研究方向使我们采取了一种新型的治疗方法，用于Beta细胞秘书途径功能障碍，以刺激细胞内蛋白质清除机制，以防止糖尿病发作和/或限制其进展。