Beta cell endoplasmic reticulum stress and its crosstalk with immune system in ty

β细胞内质网应激及其与免疫系统的串扰

• 批准号: 8751851
• 负责人: Feyza Engin
• 金额: $ 11.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751851
• 关键词: Adoptive Transfer; Affect; Animal Model; Apoptotic; Architecture; Area; Atherosclerosis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Beta Cell; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Chemicals; Child; Chronic; Coculture Techniques; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Endoplasmic Reticulum; Environmental Risk Factor; Failure; Functional disorder; Future; Gene Mutation; Goals; Grant; Homeostasis; Human; Immune; Immune Cell Activation; Immune response; Immune system; Inbred NOD Mice; Incidence; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interdisciplinary Study; Intervention; K-Series Research Career Programs; Lead; Learning; Lymphocyte; Mediating; Membrane; Mentors; Mentorship; Molecular; Molecular Chaperones; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Prevention strategy; Process; Protein Biosynthesis; Proteins; Regulation; Relative (related person); Research; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Signal Transduction; Staging; Stress; System; Testing; Therapeutic; Time; Training; United States; Work; base; career; coping; design; endoplasmic reticulum stress; improved; in vivo; insulin secretion; islet; lymphocyte proliferation; migration; mouse model; novel; pre-clinical; prevent; protein misfolding; public health relevance; research study; response; sensor; tauroursodeoxycholic acid; treatment strategy

DESCRIPTION (provided by applicant): Type 1 diabetes results from the destruction of the insulin-secreting ¿-cells by an immune mediated process. The increasing incidence of type 1 diabetes around the world, especially among children, has been of great concern. Despite intensive efforts to identify the underlying causes of this disease, it is still not clear why ¿-cels are destroyed, what triggers the initial immune destruction and how it could be prevented or reversed. Endoplasmic reticulum (ER) stress, caused by protein misfolding, chronic inflammation and environmental factors, is emerging as a novel paradigm for diabetes pathogenesis. To cope with ER stress, the Unfolded Protein Response (UPR), a signaling cascade mediated by ER membrane-localized sensors ATF6, IRE1 and PERK, is triggered to re-establish cellular homeostasis. ER stress and aberrant UPR have been shown to play a role in the pathogenesis of inflammatory and autoimmune diseases including type 2 diabetes and atherosclerosis. However, the role of ER stress and the UPR in pathophysiology and in the initiation and propagation of the autoimmune responses in T1DM remains incompletely defined. We claim that the loss of ER adaptive capacity in ¿-cells early in disease progression can lead not only to b-cell dysfunction, but also contribute to an aggravated autoimmune response. For this three- year Mentored Research Scientist Development K-Award training period, and with the guidance of my K01 mentorship team, I propose the following training and research plan: 1) a strategic four-pronged training approach to learn how to design, lead and execute a multidisciplinary research project, and 2) as the research objective of this application, collect preliminary data for a future RO1 grant. The research application has two specific aims: Aim 1: To determine the role of ATF6 in ¿-cells during different stages of disease progression. We hypothesize that losing the ATF6 branch of the UPR during diabetes progression will disrupt b-cell function, and depending on the stage of the deletion, it will also affect insulitis developmen. To test this hypothesis, we will use a recently generated mouse model that allows us to inducibly delete ATF6¿ specifically in ¿-cells at defined times during disease progression in non-obese diabetic (NOD) mice. Aim 2: To examine cell non-autonomous effects of ¿-cell ER stress on lymphocyte proliferation, activation, migration and polarization. We hypothesize that ¿-cell stress can be sensed by lymphocytes and that this extrinsic stress can lead to phenotypic and/or molecular changes in immune cells. We will test this hypothesis by using ex vivo co-culture systems and in vivo adoptive transfer experiments. The expected outcome of the proposed work is a detailed characterization of the ATF6 branch of the UPR and new understanding of a previously unstudied area of ER stress-driven cross talk between ¿-cells and immune cells. This work has the potential to make an important impact on understanding the role of ER stress in T1DM and promote development of better therapeutic and preventive strategies.

描述（由应用程序提供）：1型糖尿病是由于免疫介导的过程破坏了胰岛素分泌�-细胞的原因。全球1型糖尿病的发生率不断增加，尤其是在儿童中，引起了人们的关注。尽管努力确定了这种疾病的根本原因，但仍不清楚为什么 - 凯尔斯被破坏，是什么触发了最初的免疫侵害以及如何预防或反转。由蛋白质错误折叠，慢性感染和环境因素引起的内质网（ER）应激正在成为糖尿病发病机理的新型范式。为了应对ER应力，触发了ER膜 - 定位传感器ATF6，IRE1和PERK介导的信号级联反应（UPR），以重新建立细胞稳态。 ER应激和异常UPR已显示在包括2型糖尿病和动脉粥样硬化在内的炎症和自身免疫性疾病的发病机理中起作用。然而，ER应激和UPR在病理生理学以及T1DM自身免疫反应的主动性和传播中的作用仍然未完全定义。我们声称，疾病进展早期的ER适应能力损失不仅会导致B细胞功能障碍，而且会导致综合的自身免疫反应。在这个为期三年的指导研究科学家发展K-award培训期间，在我的K01 Mentalship团队的指导下，我提出了以下培训和研究计划：1）一种战略性的四笔记本的培训方法，以学习如何设计，领导和执行多学科研究项目，以及2）作为该应用程序的研究目标，为未来的RO1赠款收集了该应用程序。研究应用程序具有两个具体的目的：目标1：确定在疾病进展的不同阶段，ATF6在细胞中的作用。我们假设在糖尿病进展过程中失去UPR的ATF6分支将破坏B细胞功能，并且取决于缺失阶段，它也会影响胰岛炎的发育。为了检验这一假设，我们将使用最近生成的小鼠模型，该模型使我们能够在非肥胖糖尿病（NOD）小鼠中疾病进展过程中定义的时间删除ATF6。目的2：检查细胞的非自主效应 - 细胞ER应激对淋巴细胞增殖，激活，迁移和极化的影响。我们假设可以通过淋巴细胞来感测 - 细胞应力，并且这种外部应力可以导致免疫球体的表型和/或分子变化。我们将通过使用离体共培养系统和体内自适应转移实验来检验这一假设。拟议工作的预期结果是对UPR的ATF6分支的详细表征，以及对ER应力驱动的横向聊天与细胞和免疫细胞之间的先前未研究区域的新理解。这项工作有可能对理解ER压力在T1DM中的作用并促进更好的治疗和预防性策略的作用产生重要影响。