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Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth

骨形态发生蛋白作为β细胞生长的新型调节剂

基本信息

批准号：
8324525
负责人：
JAKE ALDEN KUSHNER
金额：
$ 30.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8324525
关键词：
Acute Adult Affinity BMP2 gene BMP4 Beta Cell Biological Preservation Cell Proliferation Cell physiology Cells Clinical Data Development Diabetes Mellitus Ductal Epithelium Embryo Embryonic Development FDA approved Financial compensation Fracture Gene Deletion Gene Targeting Goals Growth Growth and Development function Healed In Vitro Insulin-Dependent Diabetes Mellitus Knock-out Knockout Mice Laboratories Lead Life Ligand Binding Ligands Measurement Mediating Morphogenesis Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathway interactions Patients Pharmaceutical Preparations Phenotype Publishing Relative (related person)Research Role Signal Pathway Signal Transduction Speed Stimulation of Cell Proliferation Stimulus Techniques Technology Testing Tissues Translating Transplantation Work autocrine base bone morphogenic protein cell growth diabetes mellitus therapy embryo tissue exenatide fundamental research glucagon-like peptide 1 healing improved in vivo insulin secretion islet novel novel strategies parathyroid hormone-related protein procollagen C-endopeptidase receptor research study type I and type II diabetes

项目摘要

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.

摘要：细胞团不足在1型和2型糖尿病中都很常见。我们的长期研究目标是了解影响细胞生长的信号，以此作为糖尿病患者细胞团再生的一步病人。令人惊讶的是，人们对细胞生长是如何调控的知之甚少，也几乎没有丝裂原信号显示了对细胞质量的影响。骨形态发生蛋白(BMPs)是一种极具吸引力的促有丝分裂候选者成体细胞中的信号，因为它们在许多胚胎组织中发挥作用。没有公开发表的证据表明 BMP影响成体细胞的生长。但是，大量的体外研究表明，骨形态发生蛋白影响胚胎细胞发育。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假设BMP信号调节成年细胞的生长。我们的研究理由得到了加强，我们的初步研究：全身BMP4治疗促进体内细胞增殖，急性BMPR1A基因缺失严重降低了成人细胞的增殖。因此，具体目标如下：1.检验假设 BMPR1A信号调节成年细胞的生长。2.检验Bmpr1b信号也调节- 细胞生长。3.验证自分泌BMP4信号调节成人细胞生长的假设。为了执行我们的我们的研究将采用在我们的实验室完全实施的技术，并得到大量初步数据。因此，我们期望我们的研究可以确定骨形态发生蛋白是一种主要的有丝分裂信号。 -细胞内的途径。重要的是，FDA批准的BMP2药物已经在临床上常规使用，以加速愈合有骨折的迹象。这些研究最终可能为糖尿病患者带来基于骨形态发生蛋白的新疗法。叙述：改善对β细胞生长的了解是糖尿病研究的一个重要目标，这可能有利于糖尿病。患者，允许保留2型糖尿病患者的胰岛素分泌，或扩大胰岛用于移植给1型糖尿病患者。在这里，我们建议进行研究，从基因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，一种新的策略可能导致开发治疗糖尿病的新疗法。