Role of endoplasmic reticulum calcium in beta cell mitochondrial dysfunction, senescence, and onset of type 1 diabetes

内质网钙在 β 细胞线粒体功能障碍、衰老和 1 型糖尿病发病中的作用

• 批准号: 10537643
• 负责人: Staci A. Weaver
• 金额: $ 3.54万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-10 至 2024-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537643
• 关键词: ATP phosphohydrolase; Aging; Attenuated; Autoimmune; Autoimmunity; Automobile Driving; B-Cell Development; Beta Cell; Biological Assay; Blood Glucose; Ca(2+)-Transporting ATPase; Calcium; Cell Aging; Cell Death; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Clinical Trials; Communication; Complex; Critical Thinking; DNA Damage; Dangerousness; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Diagnosis; Disease; Economics; Endoplasmic Reticulum; Environment; Enzyme-Linked Immunosorbent Assay; Evolution; Faculty; Fellowship; Foundations; Goals; Health; Health Benefit; Hyperglycemia; Immune; Immune Targeting; Immune system; Inbred NOD Mice; Indiana; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Life; Life Expectancy; Link; Maintenance; Mediating; Membrane Potentials; Mentors; Metabolic Diseases; Mitochondria; Modeling; Molecular; Monitor; Mus; Non obese; Oral; Organelles; Oxygen Consumption; Pathway interactions; Persons; Phenotype; Play; Prevention; Production; Proteins; Public Health; Pump; Research; Role; Serum; Stress; Structure of beta Cell of islet; Technical Expertise; Techniques; Telomere Shortening; Testing; Therapeutic; Training; Tumor-infiltrating immune cells; Universities; Work; biological adaptation to stress; cell type; chemokine; chronic autoimmune disease; cost; cytokine; diabetes pathogenesis; diabetic; empowered; endoplasmic reticulum stress; experience; insulin dependent diabetes mellitus onset; insulin secretion; insulitis; islet; live cell imaging; medical schools; mitochondrial dysfunction; mitochondrial membrane; mouse model; novel; novel therapeutics; paracrine; pre-doctoral; premature; prevent; proteotoxicity; psychosocial; recruit; response; restoration; senescence; single-cell RNA sequencing; skills

PROJECT SUMMARY / ABSTRACT Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of the insulin producing β cells of the pancreas causing severe hyperglycemia. Recent evidence suggests that the β cell itself plays a complex role in T1D pathogenesis through activation of cellular senescence, which is associated with secretion of chemokines and proinflammatory cytokines (SASP) that may act to amplify recruitment of immune cells, making the β cells more vulnerable to immune attack. While senescence has been linked with mitochondrial dysfunction in other cell types, the molecular pathways leading to β cell senescence and SASP are largely unknown, leaving a critical need to determine underlying mechanisms to propel the development of novel T1D prevention therapeutics. Calcium (Ca2+) plays a vital role in β cell function, regulating key steps involved in the production and secretion of insulin. The fidelity of these tasks depends on the maintenance of Ca2+ stores, organized at both the cellular and organelle level. The endoplasmic reticulum (ER) serves as a dominant intracellular Ca2+ store, and ER Ca2+ is maintained through activity of the sarco-endoplasmic reticulum Ca2+ ATPase 2b (SERCA2) pump. We have shown previously that β cell SERCA2 expression is reduced in models of T1D, leading to diminished insulin secretion, ER stress, and increased β cell death. My preliminary data has extended these observations and linked loss of SERCA2 activity with decreased mitochondrial function and increased expression of key senescence markers. Against this background, I hypothesize that loss of ER Ca2+ via reduced SERCA2, accelerates β cell senescence and SASP via mitochondrial dysfunction driving the development of T1D. I will test this hypothesis through two specific aims. In Aim 1, I will elucidate the role of ER Ca2+ loss on islet β cell senescence, SASP, and mitochondrial function. In Aim 2, I will define whether SERCA2 activation and/or senolytic treatments, which eliminate senescent cells, can attenuate T1D onset, β cell mitochondrial dysfunction, senescence, and SASP. Completion of this project has the potential to define a novel regulatory role for β cell ER Ca2+ and mitochondrial health during the development of T1D and may inform new paradigms of T1D prevention. With this F31 Predoctoral Fellowship, I will be empowered to complete my research strategy, while also focusing on my training plan, which includes 4 main objectives: 1) Build a detailed and foundational understanding of techniques and concepts in diabetes research, 2) Build strong technical skills in live cell imaging and single cell RNA sequencing analysis, 3) Develop and cultivate mentoring skills, and 4) Enhance my critical thinking skills through written and oral scientific communication. My training plan will be supported by the experienced faculty and collaborative research environment provided by the Center for Diabetes and Metabolic Diseases and Herman B. Wells Center at the Indiana University School of Medicine. In summary, this comprehensive research strategy and training plan will set me on a trajectory to make a lasting impact in the field of T1D research.

项目总结/摘要 1型糖尿病（T1 D）的特征在于自身免疫介导的对胰岛素产生β细胞的破坏， 胰腺引起严重的高血糖症。最近的证据表明，β细胞本身起着复杂的作用， 在T1 D发病机制中的作用，通过激活细胞衰老，这与分泌 趋化因子和促炎性细胞因子（SASP），其可起到放大免疫细胞募集的作用， 使β细胞更容易受到免疫攻击。虽然衰老与线粒体有关 在其他细胞类型的功能障碍中，导致β细胞衰老和SASP的分子途径主要是 未知，因此迫切需要确定推动新型T1 D发展的潜在机制 预防治疗学钙（Ca 2+）在β细胞功能中起着至关重要的作用，调节参与β细胞功能的关键步骤。 胰岛素的产生和分泌。这些任务的保真度取决于Ca 2+储存的维持， 在细胞和细胞器水平上组织起来。内质网（ER）作为一种主要的 内质网Ca ~（2+）通过肌质内质网Ca ~（2+）的活性维持 ATP酶2b（SERCA 2）泵。我们之前已经证明，在模型中β细胞SERCA 2表达减少， 导致胰岛素分泌减少、ER应激和β细胞死亡增加。我的初步数据显示 扩展了这些观察结果，并将SERCA 2活性的丧失与线粒体功能的降低联系起来， 增加关键衰老标记物的表达。在这种背景下，我假设ER的丧失 Ca 2+通过减少SERCA 2，通过线粒体功能障碍加速β细胞衰老和SASP 推动T1 D的发展。我将通过两个具体目标来检验这个假设。在目标1中，我将阐明 ER Ca 2+丢失在胰岛β细胞衰老、SASP和线粒体功能中的作用。在目标2中，我定义 消除衰老细胞的SERCA 2激活和/或衰老清除治疗是否可以减弱T1 D 发病、β细胞线粒体功能障碍、衰老和SASP。该项目的完成有可能 定义了β细胞ER Ca 2+和线粒体健康在T1 D发展过程中的新的调节作用， 可能为T1 D预防提供新的范例。有了这个F31博士前奖学金，我将有权 完成我的研究策略，同时也专注于我的培训计划，其中包括4个主要目标：1） 建立对糖尿病研究技术和概念的详细和基础性理解，2）建立 在活细胞成像和单细胞RNA测序分析方面具有较强的技术技能，3）开发和培养 指导技能，以及4）通过书面和口头科学交流提高我的批判性思维能力。 我的培训计划将得到经验丰富的教师和合作研究环境的支持 由糖尿病和代谢疾病中心和赫尔曼B。印第安纳州大学威尔斯中心 医学院。总之，这一全面的研究战略和培训计划将使我对一个 轨迹，在T1 D研究领域产生持久影响。