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全球最重大的生物医学挑战之一。除了与糖尿病特别相关的发病率外，该疾病还与血脂异常、心血管疾病和几种类型的癌症等并发症相关，并且是美国和全球的主要死亡原因。这些观察结果突出表明，迫切需要对可以安全和选择性地增强β细胞增殖的因素进行更多的研究，以规划对抗这种疾病的治疗方法。几种胰岛素抵抗的哺乳动物模型表明β细胞具有显著的能力来增加其质量以对抗和/或延迟明显的糖尿病的发作。在这些模型中促进β细胞增殖的潜在因素的来源尚未完全探索，这是一个及时的研究领域。 我们使用联体共生和移植方法的初步数据表明，肝脏是一个潜在的生长因子来源，可以增强β细胞增殖。使用蛋白质组学和亲和素的方法，我们已经确定了这个因素作为serpinB 1。SerpinB 1能够在体外直接促进小鼠胰岛和人胰岛中β细胞的增殖。该提案的果阿是研究serpinB 1在胰岛生物学调节中的作用。我们将 本提案的目的如下：1）确定serpinB 1调节β细胞群的能力。我们将使用缺乏sepinB 1的模型或以肝脏特异性方式来检验SerpinB 1在体内调节β细胞群的假设。我们还将在糖尿病模型中测试serpinB 1逆转高血糖效应的能力。2)我们将探讨的机制，其中serpinB 1调节β细胞增殖使用体外研究，包括重组serpinB 1和serpinB 1变体对小鼠和人类胰岛细胞增殖的影响。我们将确定介导serpinB 1作用的信号通路，并将我们的方法与serpinB 1处理的胰岛的亲和素和蛋白质组学分析相结合;最后3）我们将通过研究重组serpinB 1在体外人胰岛和人源化糖尿病小鼠模型中的作用来检查serpinB 1的翻译和治疗意义。这些研究将为人类β细胞增殖提供新的视角。

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.