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（T1D）和 -2糖尿病（T2D）。但是，信号通路的性质负责年龄依赖年龄的下降 β细胞增殖仍然是一个谜，这是糖尿病治疗中的显着障碍。 Kulkarni实验室 乔斯林糖尿病中心最近报道说，肝脏分泌的SERPINB1促进了β细胞的增殖（EL Ouamari等。 2016年细胞代谢）虽然密歇根大学的Qi实验室表明Toll- 像受体2和4（TLR2/TLR4）信号通路一样，两个冗余的先天免疫信号通路， 阻止饮食诱导的β细胞复制（NAT免疫，在修订中）。在此应用程序中，Kulkarni和Qi 实验室将合作检验一个总体假设，即Serpinb1之间的拮抗相互作用 TLR2/TLR4保持平衡，有利于小鼠和人类的β细胞再生 糖尿病刺激。我们提出饮食诱导的肥胖症中的TLR2/TLR4激活serpinb1介导 β细胞复制，而同时破坏β细胞上TLR2/TLR4信号通路可能会促进β细胞 通过serpinb1依赖性方式增殖。为此，我们将（i）执行谱系跟踪以测试 TLR2/TLR4以β细胞自主方式调节β细胞复制的假设； （ii）描述 TLR2/TLR4和SERPINB1与β细胞调节中的基本机制之间的相互作用 再生; （iii）确定靶向TLR2/TLR4和SERPINB1在β细胞中的治疗潜力 使用人β细胞和胰岛增殖和再生。因此，这项研究将在 证明了代谢和先天免疫系统，两个原始系统对于长期至关重要 多细胞生物的稳态已经发展为促进对抗的合作，适应性反应 潜水员环境挑战，例如营养不良。如果成功，这项研究将有助于实现治疗 我们的发现和受益于全球数百万糖尿病患者的潜力，通过提供新颖的，无价的 治疗宽度糖尿病的治疗剂。 与人类健康的相关性：与平行小鼠模型和人类胰岛研究相关的这种应用， 将揭示新的分子和细胞机制，由代谢和先天免疫信号传导塑造 控制β细胞复制和代谢稳态的途径。因此，这项研究可能从根本上 改变我们对代谢性免疫学相互作用的看法，并保持巨大的希望 旨在治疗和逆转基础的新型疾病机制和药物靶标 糖尿病的代谢失衡。