Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration

摘要 胰腺β细胞再生是治疗胰岛素依赖型1(T1D)和 -2糖尿病(T2D)。然而，导致年龄依赖性下降的信号通路的性质(S) β细胞的增殖仍然是一个谜，是糖尿病治疗的一个重要障碍。库尔卡尼实验室位于 乔斯林糖尿病中心最近报道，从肝脏分泌的SerpinB1促进β细胞增殖(EL Ouaamari等人。细胞代谢2016)，而密歇根大学的齐实验室显示，Toll- 类似受体2和4(TLR2/TLR4)的信号通路，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免疫，修订中)。在这一应用中，库尔卡尔尼和齐 实验室将联合起来测试一个压倒一切的假设，即serpinB1之间的拮抗相互作用 TLR2/TLR4在小鼠和人的β细胞再生中均维持平衡 糖尿病引起的刺激。我们认为TLR2/TLR4在饮食诱导的肥胖中的激活阻断了SerpinB1介导的 β细胞复制同时阻断β细胞上的TLR2/TLR4信号通路可能促进β细胞 以SerpinB1依赖的方式增殖。为此，我们将(I)执行世系跟踪以测试 假设TLR2/TLR4以β细胞自主的方式调节β细胞复制；(Ii)描绘 TLR2/TLR4与丝蛋白B1的相互作用及其调控β细胞的机制 确定靶向TLR2/TLR4和SerpinB1在β细胞中的治疗潜力 使用人β细胞和胰岛进行增殖和再生。因此，这项研究将有助于 证明了新陈代谢和先天免疫系统这两个对长期至关重要的原始系统 多细胞生物体的动态平衡，已经进化成促进对 不同的环境挑战，如营养过剩。如果成功，这项研究将有助于实现治疗 我们的发现潜力巨大，并通过提供新的、无价的产品使全球数百万糖尿病患者受益 治疗广泛性糖尿病的治疗学。 与人类健康的相关性：这项应用，通过平行的小鼠模型和人类胰岛研究， 将揭示新陈代谢和先天免疫信号形成的新的分子和细胞机制 调控β细胞复制和代谢动态平衡的途径。因此，这项研究可能从根本上 改变我们对新陈代谢和先天免疫相互作用的看法，并拥有发现两者的巨大希望 旨在治疗和逆转潜在疾病的新的疾病机制和药理靶点 糖尿病患者的代谢失衡。

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.