Benefits and harms of activating ATF6 in beta cells

激活 β 细胞中 ATF6 的好处和坏处

• 批准号: 10608568
• 负责人: Laura C Alonso
• 金额: $ 45.57万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608568
• 关键词: ATF6 gene; Attention; Automobile Driving; Beta Cell; Biology; Cell Count; Cell Proliferation; Cell Survival; Cell physiology; Cellular Stress; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; DHFR gene; Data; Data Set; Diabetes Mellitus; Disease; Engineering; Exposure to; Failure; Frustration; Functional disorder; Future; Genetic; Genetic Transcription; Genomics; Glucose; Glucose Intolerance; Goals; Harm Reduction; Health; Homeostasis; Hour; Human; Impairment; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Lasers; Lead; Learning; Link; Modeling; Molecular; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmaceutical Preparations; Play; Population; Predisposition; Prevention; Process; Production; Proliferating; Proteins; Publishing; Recovery; Reporting; Resistance; Risk; Role; Stimulus; Stress; Structure of beta Cell of islet; System; Technology; Testing; Therapeutic; Time; Tissues; Uncertainty; Work; base; biological adaptation to stress; cell type; combat; diabetes pathogenesis; diabetes risk; diabetic; diabetogenic; endoplasmic reticulum stress; experimental study; genomic locus; improved; in vivo; insight; islet; novel; novel strategies; prevent; resilience; response; small molecule; tool; transcription factor

ABSTRACT Pancreatic beta cell insulin production is the critical lynchpin that determines diabetes resistance or susceptibility. ER stress is one cause of beta cell dysfunction and failure, not only in T2D but also in T1D and some forms of monogenic diabetes. Many published reports show that the ATF6 pathway, one of three principal ER stress response pathways, plays important roles in cellular adaptation to stress. In particular, ATF6 is known to drive beneficial effects including increased ER capacity, cell survival in the face of stress, and more recently evidence from our group and several others implicate ATF6 in beta cell compensatory proliferation in response to insulin demand. For these reasons, activation of ATF6 has been proposed as a potential beta cell therapeutic approach that might improve beta cell mass and insulin production capacity. We have developed two novel, exciting tools that allow us to activate ATF6 in beta cells with temporal precision, either ex vivo or in vivo in live mice. Initial experiments, however, show that when we indiscriminately activate ATF6 for an extended period of time we observe a mix of beneficial and harmful effects, in some ways reminiscent of glucotoxic beta cell failure. Specifically, we do observe evidence of increased beta cell proliferation and survival, but activating ATF6 in vivo continuously for a 14-day period leads to frank glucose intolerance due to beta cell dysfunction. Remarkably, if we allow ATF6 to turn off, beta cell function gradually returns to normal. Molecular and morphological preliminary data suggest that in vivo chronic continuous ATF6 activation mimics, in many ways, chronic beta cell stress in T2D, with similarities to mouse and human observations. As such, this model represents a tremendous opportunity to study the proximate causes of beta cell failure after chronic activation of one ER stress response pathway (ATF6), as well as a unique and exciting chance to understand the in vivo recovery process if that stress pathway activation is able to shut off. In this project we will explore the causes of beta cell failure after ATF6 activation, with in-depth molecular, morphological and tissue homeostasis experiments. We will determine the cellular and molecular bases for beta cell recovery when ATF6 is allowed to turn off. Finally, we turn our attention to the molecular mechanisms driving benefits and harms of ATF6 activation and seek to identify conditions in which beneficial responses can be separated from harmful responses, to see whether it may be possible in the future to harness ATF6 for safe therapeutic potential in diabetes treatment or prevention. If successful, this project will lead to important new insight into beta cell stress-induced diabetes, the in vivo recovery process after ATF6-induced beta cell dysfunction, the molecular mechanisms by which ATF6 drives benefits and harms, and whether it may be possible to separate benefit from harm for future therapeutic benefit.

抽象的 胰腺β细胞胰岛素的产生是决定糖尿病抵抗力或易感性的关键关键。 ER 应激是 β 细胞功能障碍和衰竭的原因之一，不仅在 T2D 中，而且在 T1D 和某些形式的糖尿病中也是如此。 单基因糖尿病。许多已发表的报告表明，ATF6 途径（三种主要 ER 应激之一） 反应途径，在细胞适应压力中发挥重要作用。特别是，已知 ATF6 可以驱动 有益的影响包括增加内质网容量、细胞在面对压力时的存活率以及最近的证据 我们小组和其他几个小组的研究表明 ATF6 参与胰岛素响应的 β 细胞代偿性增殖 要求。由于这些原因，ATF6 的激活已被提议作为一种潜在的 β 细胞治疗方法 这可能会提高β细胞质量和胰岛素生产能力。我们开发了两种新颖、令人兴奋的工具 这使得我们能够在离体或活体小鼠体内以时间精度激活 β 细胞中的 ATF6。最初的 然而，实验表明，当我们长时间不加选择地激活 ATF6 时，我们 观察到有益和有害的影响的混合体，在某些方面让人想起糖毒性β细胞衰竭。 具体来说，我们确实观察到 β 细胞增殖和存活增加的证据，但在体内激活了 ATF6 连续 14 天会因 β 细胞功能障碍而导致明显的葡萄糖不耐受。值得注意的是，如果 我们让ATF6关闭，β细胞功能逐渐恢复正常。分子和形态学初步 数据表明，体内慢性持续 ATF6 激活在许多方面模拟了慢性 β 细胞应激 T2D，与小鼠和人类的观察结果相似。因此，该模型代表了巨大的 有机会研究一种 ER 应激反应慢性激活后 β 细胞衰竭的直接原因 途径（ATF6），以及了解体内恢复过程的独特而令人兴奋的机会，如果压力 通路激活能够关闭。在这个项目中，我们将探讨 ATF6 后 β 细胞衰竭的原因 激活，通过深入的分子、形态和组织稳态实验。我们将确定 当 ATF6 被允许关闭时，β 细胞恢复的细胞和分子基础。最后，我们把注意力转向 研究驱动 ATF6 激活的益处和危害的分子机制，并寻求确定 ATF6 激活的条件 哪些有益的反应可以与有害的反应区分开来，看看这是否可能在 未来将利用 ATF6 在糖尿病治疗或预防中发挥安全治疗潜力。如果成功的话，这 该项目将对β细胞应激诱发的糖尿病、糖尿病后的体内恢复过程产生重要的新见解。 ATF6 诱导的 β 细胞功能障碍、ATF6 带来益处和危害的分子机制，以及 是否有可能将益处与危害分开以获得未来的治疗益处。