Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth

摘要： 2型糖尿病的发病原因有哪些？我们的长期研究目标是 了解影响细胞生长的信号，作为糖尿病细胞群再生的一步 患者令人惊讶的是，人们对细胞生长是如何调节的知之甚少，很少有促有丝分裂信号被发现。 被证明能影响细胞质量。骨形态发生蛋白（BMPs）是一种有吸引力的促有丝分裂因子 由于它们在许多胚胎组织中的作用，它们在成年细胞中发出信号。没有公开的证据表明 BMP影响成体细胞生长。但是，大量的体外研究表明，BMP影响 胚胎细胞发育。我们将在小鼠中使用可诱导的组织特异性基因缺失来测试 BMP信号调节成体细胞生长的假说。我们的研究的理由是加强了我们的 初步研究：全身性BMP 4治疗刺激体内细胞增殖和急性Bmpr 1a基因 缺失会严重降低成体细胞的增殖。具体目标如下：1。检验这一假设 Bmpr 1a信号调节成体细胞的生长。2.测试Bmpr 1b信号也调节的假设- 细胞生长3.测试自分泌BMP 4信号调节成体细胞生长的假设。贯彻执行党和国家的 我们将采用在我们实验室中完全实施的技术，并得到大量 初步数据。因此，我们预计我们的研究可以建立BMP作为一个主要的有丝分裂信号 细胞中的通路。重要的是，FDA批准的BMP 2药物已经在常规临床使用，以加速愈合 骨折这些研究可能最终导致糖尿病患者的新的基于BMP的疗法。说明： 更好地了解β细胞生长是一个重要的糖尿病研究目标，可能会使糖尿病受益 2型糖尿病患者的胰岛素分泌，或扩大胰岛， 移植到1型糖尿病患者身上。在这里，我们建议进行研究，从遗传学上询问 骨形态发生蛋白（BMP）信号通路在β细胞生长，一种新的策略，可以导致 糖尿病新疗法的开发。

ABSTRACT: Inadequate ¿-cell mass is common to both type 1 and type 2 diabetes. Our long-term research goal is to understand the signals that influence ¿-cell growth, as a step towards regeneration of ¿-cell mass in diabetes patients. Surprisingly little is known about how ¿-cell growth is regulated, and few mitogenic signals have been demonstrated to influence ¿-cell mass. Bone Morphogenic Proteins (BMPs) are attractive candidate mitogenic signals in adult ¿-cells because of their roles in many embryonic tissues. There is no published evidence that BMPs influence adult ¿-cell growth. But, a large number of in vitro studies indicate that BMPs influence embryonic ¿-cell development. We will use inducible tissue specific gene deletion in mice to test the hypothesis that BMP signals regulate adult ¿-cell growth. The rationale for our studies is strengthened by our preliminary studies: Systemic BMP4 treatment stimulates ¿-cell proliferation in vivo, and acute Bmpr1a gene deletion severely reduces adult ¿-cell proliferation. Hence, the following Specific Aims: 1. Test the hypothesis that Bmpr1a signals regulate adult ¿-cell growth. 2. Test the hypothesis that Bmpr1b signals also regulate ¿- cell growth. 3. Test the hypothesis that autocrine BMP4 signals regulate adult ¿-cell growth. To carry out our studies we will employ techniques that are fully implemented in our laboratory, supported by substantial preliminary data. Thus, we anticipate that our studies could establish BMPs as a major mitogenic signaling pathway in ¿-cells. Importantly, an FDA approved BMP2 drug is already in routine clinical use to speed healing of bone fractures. These studies could ultimately lead to novel BMP based therapies for diabetes patients. NARRATIVE: Improved understanding of beta-cell growth is an important diabetes research goal that could benefit diabetes patients, allowing preservation of insulin secretion in patients with type 2 diabetes, or expansion of islets for transplant into patients with type 1 diabetes. Here, we propose studies to genetically interrogate the role of the Bone Morphogenic Protein (BMP) signaling pathway in beta-cell growth, a novel strategy that could lead to the development of new therapies for diabetes.