Role of SerpinB1 in beta cell growth

描述(由申请人提供)：1型和2型糖尿病及其代谢后果仍然是当今世界范围内最重大的生物医学挑战之一。除了与糖尿病相关的疾病外，这种疾病还与血脂异常、心血管疾病和几种类型的癌症等并发症有关，是美国和世界各地的主要死亡原因。这些观察结果突出表明，迫切需要对可以安全和选择性地促进β细胞增殖的因素进行更多研究，以计划抗击这种疾病的治疗方法。几个胰岛素抵抗的哺乳动物模型表明，β细胞具有显著的能力增加其质量来对抗和/或延缓显性糖尿病的发生。在这些模型中促进β细胞增殖的潜在因素的来源还没有得到充分的探索，这是一个及时的研究领域。 我们使用异种移植和移植方法的初步数据表明，肝脏是促进β细胞增殖的生长因子的潜在来源。利用蛋白质组学和Affymetrix方法，我们已确定该因子为serpinB1。SerpinB1在体外能直接促进小鼠胰岛和人胰岛β细胞的增殖。这项建议的目的是研究serpinB1在胰岛生物学调控中的作用。我们会 解决本提案中的以下目标：1)确定serpinB1调节β细胞质量的能力。我们将使用全局缺乏sepinB1的模型或以肝脏特有的方式来检验serpinB1在体内调节β细胞质量的假设。我们还将测试serpinB1逆转糖尿病模型中高血糖的影响的能力。2)我们将通过体外研究探索serpinB1调控β细胞增殖的机制，包括重组serpinB1和serpinB1变体对小鼠和人类胰岛增殖的影响。我们将定义介导serpinB1效应的信号通路，并将我们的方法与Affymetrix和用serpinB1处理的胰岛的蛋白质组学分析结合起来；最后，我们将通过研究重组serpinB1在体外人类胰岛和造成糖尿病的人源化小鼠模型中的作用来检验serpinB1的翻译和治疗意义。总之，这些研究将为人类β细胞的增殖提供一个新的视角。

DESCRIPTION (provided by applicant): Type 1 and type 2 diabetes and its metabolic consequences continue to be among the most significant biomedical challenges worldwide today. In addition to morbidities specifically related to diabetes the disease is associated with complications such as dyslipidemia, cardiovascular disease and several types of cancer and is a leading cause of death in the US and worldwide. These observations highlight the urgent need for more research into factors that can safely and selectively enhance proliferation of beta cells to plan for therapeutic approaches to combat the disease. Several mammalian models of insulin resistance indicate that beta cell have a remarkable capacity to enhance their mass to counter and/or delay the onset of overt diabetes. The source of potential factors that promote proliferation of beta cells in these models is not fully explored and is a timely area of research. Our preliminary data using parabiosis and transplantation approaches indicates that the liver is a potential source of growth factors that can enhance beta cell proliferation. Using proteomics and affymetrix approaches we have identified this factor as serpinB1. SerpinB1 is able to directly promote the proliferation of beta cells in vitro in mouse islets and human islets. The goa of this proposal is to investigate the role of serpinB1 in the regulation of islet biology. We will address the following Aims in this proposal: 1) Determine the ability of serpinB1 to regulate beta cell mass. We will test the hypothesis that SerpinB1 modulates beta cell mass in vivo using models that lack sepinB1 globally or in a liver-specific manner. We will also test the ability of serpinB1 to reverse the effects hyperglycemia in a model of diabetes. 2) We will explore the mechanisms by which serpinB1 regulates beta cell proliferation using in vitro studies that include effects of recombinant serpinB1 and serpinB1 variants on mouse and human islet proliferation. We will define the signaling pathways that mediate the effects of serpinB1 and coupled our approach with affymetrix and proteomics analyses of islet treated with serpinB1; and, finally 3) We will examine the translational and therapeutic significance of serpinB1 by investigating the effects of recombinant serpinB1 in human islets in vitro and in a humanized mouse model that is made diabetic. Together these studies will provide a novel perspective on human beta cell proliferation.