Beta Catenin Regulation of Skeletal Muscle Hypertrophy

描述(由申请人提供)：这是针对NIAMS建筑跨学科研究团队(BIRT)修订奖RFA-AR-13-003提交的修订后的申请，我们的父母资助“骨骼肌肥大的β-连环蛋白调节”。我们和Dasarathy博士建立了一个跨学科的研究团队，Dasarathy博士是一名移植肝病专家，联合受聘于克利夫兰诊所勒纳研究所的病理生物学系。除了他的临床职责，达萨拉西博士还领导了一个积极的研究项目，调查由肝硬变导致的骨骼肌石棺减少的分子和代谢机制。这项工作发现，肝硬变引起的高氨血症导致肌抑素表达增加，蛋白质合成减少，从而导致骨质疏松症。在C2C12肌管中的初步数据表明，过量表达？-catenin能够阻断对氨的反应而增加的myostatin的表达。基于这一初步数据，我们建议在本次修订中检验以下假设：过量表达连环蛋白将防止高氨血症诱导的肌肉生长抑素表达所引起的有害影响(蛋白质合成减少，肌肉质量损失)。为了验证这一假设，我们将追求以下目标：确定连环蛋白的过度表达是否能够保护骨骼肌免受高氨血症的影响。将进行体外和体内实验，以确定过量表达连环蛋白是否能够减轻氨离子诱导的肌肉生长抑素表达的有害影响。拟议的体外和体内研究有望证明，过量表达？-catenin能够通过抑制myostatin的表达来挽救肉瘤形成的表型。这些拟议的实验将最初提议的范围扩展到通过连环蛋白调节核糖体生物生成的范围，以检验连环蛋白预防肝硬变引起的石棉减少的能力。鉴于最近的发现，β-连环蛋白可能提供一种机制来挽救与肝硬变相关的肌块丢失的概念具有重要的临床意义。 能够激活连环蛋白信号的小分子。此外，根据该奖项产生的数据预计将作为R01拨款申请的基础，以响应PA-12-208“骨骼肌收缩以外的功能”，该法案旨在促进“导致保护或治疗常见疾病和状况的新战略”的研究。

DESCRIPTION (provided by applicant): This is a revised application to our parent grant "Beta-catenin regulation of skeletal muscle hypertrophy" being submitted in response to RFA-AR-13-003, NIAMS Building Interdisciplinary Research Team (BIRT) Revision Awards. We have established an interdisciplinary research team with Dr. Dasarathy, a transplant hepatologist with a joint appointment in the Department of Pathobiology at the Lerner Research Institute in the Cleveland Clinic. In addition to his clinical duties, Dr. Dasarathy heads an active research program investigating the molecular and metabolic mechanisms underlying skeletal muscle sarcopenia induced by cirrhosis. This work has found that hyperammonemia caused by cirrhosis leads to sarcopenia as the result of increased myostatin expression and decreased protein synthesis. Preliminary data in C2C12 myotubes showed that over- expression of ¿-catenin was able to block the increase in myostatin expression in response to ammonium. Based on this preliminary data, we propose in this revision to test the hypothesis that over-expression of ¿-catenin will prevent the deleterious effects (decreased protein synthesis, loss of muscle mass) caused by hyperammonemia-induced myostatin expression. To test this hypothesis, the following aim will be pursued: Determine if over-expression of ¿-catenin is able to protect skeletal muscle against hyperammonemia. Both in vitro and in vivo experiments will be performed to determine if over-expression of ¿-catenin is capable of mitigating the deleterious effects of myostatin expression induced by ammonium. The proposed in vitro and in vivo studies are expected to demonstrate that over-expression of ¿-catenin is capable of rescuing the sarcopenic phenotype by repressing myostatin expression. These proposed experiments extend the scope of the original proposal beyond the regulation of ribosome biogenesis by ¿-catenin to examine the ability of ¿-catenin to prevent cirrhosis-induced sarcopenia. The notion that ¿-catenin may provide a mechanism for rescuing the loss of muscle mass associated with cirrhosis has significant clinical implication given the recent identification of small molecules capable of activating ¿-catenin signaling. In addition, the data generated under this award are expected to serve as the basis for an R01 grant application in response to PA-12-208 "Functions of Skeletal Muscle beyond Contractions" which seeks to promote research that "leads to novel strategies to protect or treat common diseases and conditions".