Endogenous Betacellulin Signaling in Beta-cell Biology

描述(由申请人提供)： 人类胰岛移植的最新进展显示出作为治疗胰岛素依赖型糖尿病的一种方法的巨大前景。然而，在开发合适的策略用于体外扩张胰岛或刺激糖尿病患者残余胰腺组织内新的胰岛生长之前，β细胞替代疗法的临床潜力将无法实现。众所周知，某些营养物质和生长因子可以诱导胰岛β细胞的生长。ErbB受体家族在包括胰腺在内的许多组织的发育、分化、增殖和存活中起着重要作用。ErbB受体基因消融研究表明ErbB信号在β细胞生物学中具有重要的增殖作用，但这些研究因在这些受体缺失的小鼠中发现的严重缺陷而受阻。EGF相关肽生长因子家族的成员结合并激活ErbB受体。每个ErbB配体都有不同的ErbB受体结合特异性，可以激活独特的下游信号通路来产生不同的生物反应。例如，外源重组β细胞蛋白(BTC)在体外和体内模型中都可以独特地诱导β细胞新生、增殖和分化。然而，值得注意的是，内源性ErbB配体前体具有不同的信号功能，释放可溶性配体的顺序过程是ErbB受体信号转导中的一个基本调节事件；这一调节步骤不能通过添加外源重组生长因子来重复。包括BTC在内的某些ErbB配体缺陷小鼠的产生和存活为研究单个内源性ErbB配体在β细胞生物学中的特异性和/或互补性作用提供了重要的遗传学工具。 我研究的长期目标是确定不同内源性ErbB配体在β细胞生物学中的独特细胞和生化功能。这项资助计划的具体目标是研究内源性BTC信号在β细胞增殖、分化、新生和存活中的作用。本申请的具体目的1将描述BTC前体在β细胞中的调节和顺序处理。第二个特定目的是研究不同的BTC裂解产物在体外对β细胞增殖和分化的信号潜力。在具体目标3中，将单独使用BTC/-缺陷小鼠或在EGFR wa2/wa2和/或组合ErbB配体缺失的遗传背景下，研究BTC在体内β细胞发育和新生以及维持β细胞质量中的作用。这些研究的结果应该会加强我们对BTC信号在β细胞生物学中的作用以及它在人类β细胞替代疗法中的应用的理解。

DESCRIPTION (provided by applicant): Recent advances in human islet transplantation have shown great promise as an approach to treat insulin-dependent diabetes. However, the clinical potential of beta-cell replacement therapies will not be realized until appropriate strategies have been developed for the expansion of pancreatic islets ex vivo or for stimulating new islet growth within residual pancreatic tissue of diabetic patients. It is known that certain nutrients and growth factors can induce pancreatic beta-cell growth. The ErbB receptor family plays a fundamental role in the development, differentiation, proliferation and survival of many tissues including the pancreas. ErbB receptor gene ablation studies have suggested an important proliferative role for ErbB signaling in beta-cell biology but these studies have been hindered by the severity of defects found in these receptor-null mice. Members of the EGF-related peptide growth factor family bind to and activate ErbB receptors. Each ErbB ligand has distinct ErbB receptor binding specificities and can activate unique downstream signaling pathways to generate diverse biological responses. For example, exogenous, recombinant betacellulin (BTC) can uniquely induce beta-cell neogenesis, proliferation and differentiation in both in vitro and in vivo models. However, it is important to note that endogenous ErbB ligand precursors have distinct signaling functions and that sequential processing to release soluble ligand is a fundamental regulatory event in ErbB receptor signaling; a regulatory step which can not be duplicated by addition of exogenous recombinant growth factors. The generation and viability of mice deficient in certain ErbB ligands including BTC provides important genetic tools to investigate the specific and/or complementary roles of individual endogenous ErbB ligands in beta-cell biology. The long-term objectives of my research are to determine the unique cellular and biochemical functions of different endogenous ErbB ligands in beta-cell biology. The specific goals of this grant proposal are to investigate the roles of endogenous BTC signaling in beta-cell proliferation, differentiation, neogenesis and survival. Specific aim 1 of this application will characterize the regulated and sequential processing of BTC precursor in beta cells. The second Specific aim will examine the signaling potential of different BTC cleavage products in beta-cells proliferation and differentiation in vitro. In Specific aim 3, the role of BTC in beta-cell development and neogenesis as well as maintenance of beta-cell mass in vivo will be examined utilizing Btc-/-deficient mice alone or under EGFR wa2/wa2 and/or combinatorial ErbB ligand null genetic backgrounds. The results of these studies should enhance our understanding of the role of BTC signaling in beta-cell biology and its application to human beta-cell replacement therapies.