Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration

总结 胰腺β细胞再生是治疗胰岛素依赖型1（T1 D）和糖尿病的一种有前途的方法。 -2型糖尿病（T2 D）。然而，负责年龄依赖性下降的信号通路的性质 β细胞增殖的机制仍然是一个谜，是糖尿病治疗中的一个重大障碍。Kulkarni实验室， Joslin糖尿病中心最近报道，从肝脏分泌的SerpinB 1促进β细胞增殖（El Ouaamari et al. Cell Metabolism 2016），而密歇根大学的Qi实验室表明，Toll- 与受体2和4（TLR 2/TLR 4）信号通路一样，两个冗余的先天免疫信号通路， 阻断饮食诱导的β细胞复制（Nat Immunol，修订中）。在本申请中，Kulkarni和Qi 实验室将合作测试一个总体假设，即SerpinB 1之间的拮抗作用 和TLR 2/TLR 4维持有利于小鼠和人中β细胞再生的平衡。 致糖尿病的刺激我们认为，TLR 2/TLR 4在饮食诱导的肥胖中的激活阻断了SerpinB 1介导的 β细胞复制同时阻断β细胞上的TLR 2/TLR 4信号通路可能促进β细胞增殖， 通过SerpinB 1依赖的方式增殖。为此，我们将（i）执行沿袭跟踪以测试 TLR 2/TLR 4以β细胞自主方式调节β细胞复制的假设;（ii）描述了TLR 2/TLR 4在β细胞中的作用。 TLR 2/TLR 4与SerpinB 1在β细胞调节中的相互作用及其机制 （iii）确定靶向TLR 2/TLR 4和SerpinB 1在β细胞中的治疗潜力 使用人β细胞和胰岛的增殖和再生。因此，这项研究将有助于 证明了代谢和先天免疫系统，两个对长期至关重要的原始系统， 多细胞生物体内平衡，已经进化到促进合作，适应性反应， 各种环境挑战，如营养过剩。如果成功，这项研究将有助于实现治疗 我们的发现的潜力，并通过提供新颖的，宝贵的， 用于治疗广泛分布的糖尿病的治疗剂。 与人类健康的相关性：本申请采用平行小鼠模型和人类胰岛研究， 将揭示新的分子和细胞机制，由代谢和先天免疫信号塑造 这是一种调节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 改变了我们对代谢-先天免疫相互作用的看法，并为揭示这两个方面带来了巨大的希望。 新的疾病机制和药理学靶点，旨在治疗和逆转潜在的 糖尿病的代谢失衡。

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.