Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration

SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用

• 批准号: 10378332
• 负责人: ROHIT N. KULKARNI
• 金额: $ 20.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378332
• 关键词: Adult; B Cell Proliferation; Beta Cell; Blood Vessels; CDKN2A gene; Cell Cycle; Cellular Metabolic Process; Data; Diabetes Mellitus; Diet; Disease; Equilibrium; Etiology; Genetic; Homeostasis; Human; Immune; Immune signaling; Individual; Innate Immune System; Insulin; Insulin Resistance; Knockout Mice; Laboratories; Ligands; Liver; MEKs; Mediating; Metabolic; Michigan; Modeling; Molecular; Mus; Natural Immunity; Natural regeneration; Nature; Nuclear; Organism; Overnutrition; Patients; Peripheral; Pharmacology; Qi; Recombinants; Regenerative capacity; Regulation; Reporting; Signal Pathway; Signal Transduction; Stimulus; Structure of beta Cell of islet; System; TLR2 gene; TLR4 gene; Testing; Therapeutic; Time; Universities; Work; age related; aged; beta cell replacement; cell injury; cell regeneration; cell replacement therapy; diabetes mellitus therapy; diabetic patient; diabetogenic; diet-induced obesity; efficacy testing; emerging adult; glycemic control; health application; infancy; innovation; insight; islet; mouse model; new therapeutic target; novel; response; restoration; translational study

SUMMARY Pancreatic β cell regeneration is a promising approach for the treatment of insulin dependent type-1 (T1D) and -2 diabetes (T2D). However, the nature of the signaling pathway(s) responsible for the age-dependent decline of β cell proliferation remains an enigma, a significant roadblock in diabetes therapy. The Kulkarni laboratory at Joslin Diabetes Center recently reported that SerpinB1 secreted from the liver promotes β cell proliferation (El Ouaamari et al. Cell Metabolism 2016) while the Qi laboratory at the University of Michigan showed that Toll- Like Receptors 2 and 4 (TLR2/TLR4) signaling pathways, two redundant innate immune signaling pathways, block diet-induced β cell replication (Nat Immunol, under revision). In this application, the Kulkarni and Qi laboratories will team up to test an overarching hypothesis that the antagonistic interplay between SerpinB1 and TLR2/TLR4 maintains a balance in favor of β cell regeneration in both mice and humans under diabetogenic stimuli. We propose that TLR2/TLR4 activation in diet-induced obesity blocks SerpinB1-mediated β cell replication while simultaneous disruption of TLR2/TLR4 signaling pathways on β cells may promote β cell proliferation via SerpinB1-dependent manner. To this end, we will (i) perform lineage tracing to test the hypothesis that TLR2/TLR4 regulates β cell replication in a β cell autonomous manner; (ii) delineate the interplay between TLR2/TLR4 and SerpinB1 and the underlying mechanism in the regulation of β cell regeneration; and (iii) determine the therapeutic potential of targeting TLR2/TLR4 and SerpinB1 in β cell proliferation and regeneration using human β cells and islets. Hence, this study will be instrumental in demonstrating that metabolic and innate immune systems, two primitive systems critical for the long-term homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges such as overnutrition. If successful, this study will help realize therapeutic potential of our discoveries and benefit millions of diabetic patients worldwide by delivering novel, invaluable therapeutics for the treatment of widespread diabetes. RELEVANCE TO HUMAN HEALTH: This application, with parallel mouse models and human islets studies, will reveal novel molecular and cellular mechanisms, shaped by metabolic and innate immunity signaling pathways, which govern β cell replication and metabolic homeostasis. Hence, this study may fundamentally change our views of metabolic-innate immune interactions, and hold tremendous promise to uncover both novel disease mechanisms and pharmacological targets aimed at treating and reversing the underlying metabolic imbalances in diabetes.

概括 胰腺 β 细胞再生是治疗胰岛素依赖型 1 型 (T1D) 和 -2 型糖尿病 (T2D)。然而，导致年龄依赖性衰退的信号通路的性质 β细胞增殖的影响仍然是一个谜，是糖尿病治疗的一个重要障碍。库尔卡尼实验室位于 Joslin糖尿病中心最近报道肝脏分泌的SerpinB1促进β细胞增殖（El 瓦马里等人。 Cell Metabolism 2016）而密歇根大学的 Qi 实验室表明 Toll- 与受体 2 和 4 (TLR2/TLR4) 信号通路一样，两条冗余的先天免疫信号通路， 阻止饮食诱导的 β 细胞复制（Nat Immunol，修订中）。在此应用中，Kulkarni 和 Qi 实验室将联手测试一个总体假设，即 SerpinB1 之间的拮抗相互作用 在小鼠和人类中，TLR2/TLR4 保持有利于 β 细胞再生的平衡 致糖尿病的刺激。我们认为饮食诱导的肥胖中 TLR2/TLR4 的激活会阻断 SerpinB1 介导的 β细胞复制，同时破坏β细胞上的TLR2/TLR4信号通路可能促进β细胞 通过 SerpinB1 依赖性方式增殖。为此，我们将 (i) 执行谱系追踪来测试 假设TLR2/TLR4以β细胞自主方式调节β细胞复制； (二) 划定 TLR2/TLR4与SerpinB1的相互作用及其调节β细胞的机制 再生; (iii) 确定靶向 TLR2/TLR4 和 SerpinB1 在 β 细胞中的治疗潜力 使用人类 β 细胞和胰岛进行增殖和再生。因此，这项研究将有助于 证明代谢和先天免疫系统这两个对长期免疫至关重要的原始系统 多细胞生物体的稳态，已经进化到促进合作性的、适应性的反应 营养过剩等多种环境挑战。如果成功，这项研究将有助于实现治疗 我们的发现的潜力，并通过提供新颖、宝贵的药物使全世界数百万糖尿病患者受益 用于治疗广泛糖尿病的疗法。 与人类健康的相关性：该应用程序通过并行小鼠模型和人类胰岛研究， 将揭示由代谢和先天免疫信号塑造的新颖的分子和细胞机制 途径，控制 β 细胞复制和代谢稳态。因此，本研究可能从根本上 改变我们对代谢-先天免疫相互作用的看法，并有望揭示这两者 旨在治疗和逆转潜在疾病的新疾病机制和药理学靶点 糖尿病的代谢失衡。