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.

摘要 胰腺β细胞胰岛素的产生是决定糖尿病抵抗或易感性的关键。 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 单基因糖尿病许多已发表的报告表明，三种主要的ER应激之一的ATF6途径， 反应途径，在细胞适应压力中起着重要作用。具体地，已知ATF 6驱动 有益的影响，包括增加ER能力，细胞在面对压力时的存活，以及最近的证据 来自我们小组和其他几个小组的研究表明，ATF6参与了β细胞对胰岛素应答的代偿性增殖 需求由于这些原因，已经提出激活ATF6作为潜在的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的令人兴奋的工具 这使得我们能够在离体或活小鼠体内以时间精确度激活β细胞中的ATF6。初始 然而，实验表明，当我们不加选择地激活ATF6一段时间后， 观察有益和有害的影响，在某些方面让人想起葡萄糖毒性β细胞衰竭。 具体地说，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ATF 6， 连续14天导致由于β细胞功能障碍而导致的明显的葡萄糖耐受不良。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，在体内慢性持续的ATF6活化在许多方面模拟了慢性β细胞应激， T2D，与小鼠和人类观察结果相似。因此，这种模式代表了一种巨大的 有机会研究一种ER应激反应慢性激活后β细胞衰竭的近因 途径（ATF6），以及一个独特的和令人兴奋的机会，了解体内恢复过程，如果压力 通路激活能够被关闭。在这个项目中，我们将探讨ATF6后β细胞衰竭的原因。 通过深入的分子、形态学和组织稳态实验，康贝特人将以 当允许关闭ATF6时，β细胞恢复的细胞和分子基础。最后，我们把注意力 了解驱动ATF 6激活的益处和危害的分子机制，并寻求确定其中的条件 哪些有益的反应可以从有害的反应中分离出来，看看是否有可能在 未来利用ATF 6在糖尿病治疗或预防中的安全治疗潜力。如果成功，这 该项目将导致对β细胞应激诱导的糖尿病的重要新见解，在体内恢复过程后， ATF6诱导的β细胞功能障碍，ATF6驱动益处和危害的分子机制，以及 是否有可能为了将来的治疗益处而将益处与危害分开。