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。除了与糖尿病特别相关的发病外，该疾病还与血脂异常、心血管疾病和几种癌症等并发症相关，是美国和全世界死亡的主要原因。这些观察结果强调，迫切需要对能够安全、选择性地增强 β 细胞增殖的因素进行更多研究，以制定对抗该疾病的治疗方法。几种哺乳动物的胰岛素抵抗模型表明，β细胞具有显着的增强其质量以对抗和/或延迟明显糖尿病发作的能力。在这些模型中促进β细胞增殖的潜在因素的来源尚未得到充分探索，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，肝脏是可以增强β细胞增殖的生长因子的潜在来源。使用蛋白质组学和 affymetrix 方法，我们已将该因子鉴定为 serpinB1。 SerpinB1能够在体外直接促进小鼠胰岛和人类胰岛中β细胞的增殖。该提案的目的是研究 serpinB1 在胰岛生物学调节中的作用。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 或以肝脏特异性方式的模型来测试 SerpinB1 在体内调节 β 细胞质量的假设。我们还将测试 serpinB1 在糖尿病模型中逆转高血糖影响的能力。 2）我们将通过体外研究探索serpinB1调节β细胞增殖的机制，包括重组serpinB1和serpinB1变体对小鼠和人胰岛增殖的影响。我们将定义介导 serpinB1 作用的信号通路，并将我们的方法与 affymetrix 和经 serpinB1 处理的胰岛的蛋白质组学分析相结合；最后 3) 我们将通过研究重组 serpinB1 在体外人类胰岛和糖尿病人源化小鼠模型中的影响，来检验 serpinB1 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.