Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth

描述（由申请人提供）：1型和2型糖尿病患者的细胞质量不足是常见的。我们的长期研究目标是了解影响细胞生长的信号，作为糖尿病患者细胞群再生的一步。令人惊讶的是， 细胞的生长受到调节，很少有促有丝分裂信号被证明影响细胞质量。骨形态发生蛋白（BMPs）由于其在许多胚胎组织中的作用，是成体细胞中有吸引力的候选促有丝分裂信号。没有公开的证据表明BMPs影响成人 - 细胞生长但是，大量的体外研究表明BMP影响胚胎细胞的发育。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设。我们的初步研究加强了我们研究的基本原理：全身性BMP 4治疗刺激体内细胞增殖，急性Bmpr 1a基因缺失严重降低成人细胞增殖。具体目标如下：1。测试Bmpr 1a信号调节成体细胞生长的假设。2.测试Bmpr 1b信号也调节细胞生长的假设。3.测试自分泌BMP 4信号调节成体细胞生长的假设。为了进行我们的研究，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的支持。因此，我们预计我们的研究可以建立骨形成蛋白作为一个主要的有丝分裂信号通路在？细胞。重要的是，FDA批准的BMP 2药物已经在临床上用于加速骨折愈合。这些研究可能最终导致糖尿病患者的新的基于BMP的疗法。公共卫生相关性：改善对β细胞生长的理解是一个重要的糖尿病研究目标，可以使糖尿病患者受益，允许2型糖尿病患者的胰岛素分泌得以保留，或胰岛的扩增以移植到1型糖尿病患者体内。在这里，我们提出的研究从遗传学上询问骨形态发生蛋白（BMP）信号通路在β细胞生长中的作用，这是一种可能导致糖尿病新疗法开发的新策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.