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（由申请人提供）：1型糖尿病是由免疫介导过程破坏胰岛素分泌细胞引起的。1型糖尿病的发病率在世界各地，特别是儿童中的发病率不断增加，一直备受关注。尽管为确定这种疾病的根本原因作出了大量努力，但仍然不清楚为什么免疫系统被破坏，是什么触发了最初的免疫破坏以及如何预防或逆转。由蛋白质错误折叠、慢性炎症和环境因素引起的内质网（ER）应激正在成为糖尿病发病机制的新范式。为了科普内质网应激，未折叠蛋白反应（UPR），一个由内质网膜定位传感器ATF 6，IRE 1和PERK介导的信号级联反应，被触发以重建细胞内稳态。ER应激和异常UPR已被证明在炎症和自身免疫性疾病（包括2型糖尿病和动脉粥样硬化）的发病机制中起作用。然而，ER应激和UPR在T1 DM的病理生理学和自身免疫反应的启动和传播中的作用仍不完全确定。我们认为，在疾病进展的早期，ER细胞适应能力的丧失不仅会导致B细胞功能障碍，而且会导致自身免疫反应的加重。对于这个为期三年的指导研究科学家发展K奖培训期，在我的K 01导师团队的指导下，我提出了以下培训和研究计划：1）一个战略性的四管齐下的培训方法，学习如何设计，领导和执行多学科研究项目，2）作为本申请的研究目标，为未来的RO 1赠款收集初步数据。该研究应用有两个具体目标：目标1：确定ATF 6在疾病进展的不同阶段在细胞中的作用。我们假设在糖尿病进展过程中丢失UPR的ATF 6分支会破坏b细胞功能，并且根据缺失的阶段，它也会影响胰岛炎的发展。为了验证这一假设，我们将使用最近生成的小鼠模型，该模型允许我们在非肥胖糖尿病（NOD）小鼠的疾病进展期间的规定时间内诱导性删除<$-细胞中的ATF 6 <$<$。目的2：研究细胞ER应激对淋巴细胞增殖、活化、迁移和极化的细胞非自主影响。我们假设，- 细胞应激可以被淋巴细胞感知，并且这种外在应激可以导致免疫细胞的表型和/或分子变化。我们将使用体外共培养系统和体内过继转移实验来检验这一假设。拟议的工作的预期成果是详细表征的ATF 6分支的普遍定期审议和新的理解以前未研究的领域ER应力驱动的串扰之间的细胞和免疫细胞。这项工作有可能对理解ER应激在T1 DM中的作用产生重要影响，并促进更好的治疗和预防策略的发展。