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，在开发出用于离体扩增胰岛或用于刺激糖尿病患者的残余胰腺组织内的新胰岛生长的适当策略之前，β细胞替代疗法的临床潜力将不会实现。已知某些营养素和生长因子可以诱导胰腺β细胞生长。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，但这些研究受到这些受体缺失小鼠中发现的缺陷严重程度的阻碍。EGF相关肽生长因子家族的成员结合并激活ErbB受体。每个ErbB配体具有不同的ErbB受体结合特异性，并可以激活独特的下游信号传导途径，以产生不同的生物反应。例如，外源性重组β细胞素（BTC）可以在体外和体内模型中独特地诱导β细胞新生、增殖和分化。然而，重要的是要注意，内源性ErbB配体前体具有不同的信号传导功能，并且释放可溶性配体的顺序加工是ErbB受体信号传导中的基本调节事件;该调节步骤不能通过添加外源性重组生长因子来复制。包括BTC在内的某些ErbB配体缺陷小鼠的产生和存活力提供了重要的遗传工具，以研究单个内源性ErbB配体在β细胞生物学中的特异性和/或互补作用。 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。这项拨款提案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将表征BTC前体在β细胞中的受调节和顺序加工。第二个具体目标将检查不同BTC切割产物在体外β细胞增殖和分化中的信号传导潜力。在具体目标3中，将使用单独或在EGFR wa 2/wa 2和/或组合ErbB配体无效遗传背景下的Btc-/-缺陷小鼠来检查BTC在体内β细胞发育和新生以及β细胞群维持中的作用。这些研究的结果应该增强我们对BTC信号传导在β细胞生物学中的作用及其在人类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.