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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：
10647830
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/10647830
关键词：
Anabolism Animals Area Autophagocytosis 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 Failure Functional disorder Genes Genetic Glucose Golgi Apparatus Grant Homeostasis Hormones Human Hyperactivity INS gene Insulin Insulin deficiency Knockout Mice 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 biological adaptation to stress cell dedifferentiation dalton diabetes pathogenesis diabetes risk endoplasmic reticulum stress follow-up islet manufacture mutant non-diabetic novel therapeutic intervention preproinsulin prevent protein degradation recruit restraint 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.

胰腺细胞合成大量的胰岛素。越来越多的证据表明，胰岛素生物合成中的任何缺陷（遗传的或后天的）都可能导致糖尿病。我们知道胰岛素的生物合成始于胰岛素前原的翻译。这个短暂的前体必须转运到内质网（ER），切除信号肽，并适当折叠胰岛素原，才能成功地从内质网出口到远端分泌途径，在这一途径中，胰岛素原转化为胰岛素并最终在分泌颗粒中储存。相反，不成功的分子可能在它们被转运到内质网之前就被降解了，或者可能被阻止从内质网顺行输出——事实上，强有力的证据表明错误折叠的胰岛素原分子是降解的目标。分泌途径蛋白降解还涉及其他内源性底物，这些底物有助于分化的胰腺细胞表型。这个多项目的竞争延续。R01将有助于阐明三种主要的分泌途径蛋白处置机制——易位前降解；er相关降解（ERAD）；和自噬-都对正常的β细胞功能至关重要。这一建议延续了三位紧密合作研究者（Qi, Tsai, Arvan）长期以来的合作关系，他们正是这些过程的专家：胰岛素前原易位进入内质网管，随后折叠/错误折叠胰岛素原，通过ERAD的分泌途径蛋白质降解，以及我们认为主要是内质网自噬（ER-phagy）的内质网到溶酶体降解途径。我们有充分的理由相信，由于胰岛素不足，这些质量控制机制的缺陷与2型糖尿病（T2D）有关，这一信念得到了初步数据的支持。在这个建议中，我们试图检查三个相互关联的区域，这些区域与胰腺β细胞的早期分泌途径有关。首先，我们将继续研究胰岛素前原在内质网膜上的移位不正常与胰岛素前和胰岛素生物合成不足直接相关，从而直接导致糖尿病。其次，我们将对一些显著的初步数据进行后续研究，这些数据表明，胰腺β细胞的去分化是由ERAD有效功能的丧失引发的，也直接导致胰岛素缺乏型糖尿病。最后，我们不仅深入研究了引发错误折叠胰岛素原的ER吞噬降解的内质网因子，而且我们还提出了对无效或不适当的ER吞噬如何引发β细胞衰竭的更深入的理解，这也直接导致胰岛素缺乏性糖尿病。这些新的研究方向引导我们寻求一种新的治疗方法来治疗β细胞分泌通路功能障碍，重点是刺激细胞内蛋白清除机制，以预防糖尿病的发生和/或限制其进展。