C6ORF32, AN HDAC6-BINDING PROTEIN THAT REGULATES MYOBLAST DIFFERENTIATION

C6ORF32，一种调节成肌细胞分化的 HDAC6 结合蛋白

基本信息

批准号：
8185253
负责人：
EMANUELA GUSSONI
金额：
$ 39.08万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8185253
关键词：
Ablation Acetylation Affect Binding Binding Proteins Cell Communication Cell Nucleus Cell fusion Cells Computer Analysis Cytoplasm Cytoskeleton Data Defect Development Down-Regulation Event Future Gene Expression Gene Proteins Genes Genetic Transcription Giant Cells Goals HDAC6 gene Histone Deacetylase Histones Homeostasis Human In Vitro Laboratories Lysine Messenger RNA Metabolism Mononuclear Muscle Muscle Cells Muscle Development Muscle Fibers Myoblasts Myogenin Names Natural regeneration Nuclear Pathway interactions Play Process Protein Family Proteins Regulation Reporting Role Screening procedure Skeletal Muscle Stem cells Tissues Transcript Transcription Coactivator Transcription Repressor/Corepressor Tubulin Work Yang cell motility computerized data processing fetal in vivo in vivo Model injured progenitor protein activation repaired transcription factor trophoblast

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle is comprised of multinucleated syncytia formed by the fusion of myoblasts. Through microarray studies, it was found that expression of C6ORF32 is upregulated early during human myoblast fusion, when myotubes contain between 2-5 myonuclei (Cerletti et al., 2006). Downregulation of C6ORF32 expression causes a block in myoblast fusion due to a significant decrease in myogenin expression (Yoon et al., 2007). By computational analyses, the predicted C6ORF32 protein contains only one domain of known function, a putative HDAC-binding domain. It was found that C6ORF32 binds to HDAC6, a class IIb HDAC known for its function in promoting cell motility. It is hypothesized that HDAC6 and C6ORF32 are functionally connected, and the interaction between HDAC6 and C6ORF32 positively regulates myogenic differentiation by reducing the de-acetylation activity of HDAC6. The regulatory connection between HDAC6 and C6ORF32 in skeletal muscle will be studied both in vitro and in vivo via the following specific aims: 1) Define the critical binding region of C6ORF32 to HDAC6, and demonstrate that binding of these two proteins occurs in vivo; 2) Determine if HDAC6 regulates myoblast differentiation by modulating C6ORF32 acetylation/de-acetylation; 3) Evaluate if C6ORF32 regulates myoblast differentiation by modulating HDAC6 activity; 4) Determine if ablation of C6ORF32 expression in vivo yields to defects in muscle development, function and regeneration by affecting HDAC6 function. These studies will constitute the groundwork for understanding whether future pharmacological therapies targeting the regulatory interaction between C6ORF32 and HDAC6 are amenable to enhance myogenic repair. PUBLIC HEALTH RELEVANCE: C6ORF32 is an unnamed protein upregulated during fusion of human myoblasts. Previous studies in our laboratory have indicated that C6ORF32 might be involved in myogenic differentiation. More recent data indicates that C6ORF32 binds HDAC6, a critical HDAC known to regulate cell motility and cell-cell interactions. The current application will dissect the regulatory connection between HDAC6 and C6ORF32, and how this connection affects myogenic differentiation. This goal will be achieved through in vitro and in vivo studies. The proposed work will open the possibility of modulating the HDAC6-C6ORF32 regulatory interaction to enhance muscle cell fusion, with the broader scope of using C6ORF32 as a new target for muscle repair.

描述（由申请人提供）：骨骼肌由肌细胞融合形成的多核合成肌组成。通过微阵列研究，发现在人体成肌细胞融合期间，C6ORF32的表达在2-5个肌核中含有2-5个（Cerletti et al。，2006）。 C6ORF32表达的下调导致肌细胞融合的块，这是由于肌蛋白素表达显着降低（Yoon等，2007）。通过计算分析，预测的C6ORF32蛋白仅包含一个已知功能的一个域，一个推定的HDAC结合域。发现C6ORF32与HDAC6结合，HDAC6是IIB级HDAC，以其在促进细胞运动中的功能而闻名。假设HDAC6和C6ORF32在功能上连接，并且HDAC6和C6ORF32之间的相互作用通过降低HDAC6的去乙酰化活性来积极调节肌源分化。将通过以下特定目的研究骨骼肌中HDAC6和C6ORF32之间的调节连接：1）定义C6ORF32与HDAC6的临界结合区域，并证明这两种蛋白在体内的结合发生在体内； 2）确定HDAC6是否通过调节C6ORF32乙酰化/去乙酰化来调节成肌细胞分化； 3）评估C6ORF32是否通过调节HDAC6活性来调节成肌细胞分化； 4）确定C6ORF32表达在体内的消融是否会通过影响HDAC6功能而产生肌肉发育，功能和再生的缺陷。这些研究将构成理解针对C6ORF32和HDAC6之间调节相互作用的未来药理学疗法的基础，以增强肌源性修复。公共卫生相关性：C6ORF32是人类成肌细胞融合期间上调的一种未命名蛋白质。我们实验室的先前研究表明，C6ORF32可能参与了肌源分化。最近的数据表明，C6ORF32结合HDAC6，这是一种已知调节细胞运动性和细胞 - 细胞相互作用的关键HDAC。当前的应用将剖析HDAC6和C6ORF32之间的调节连接，以及该连接如何影响肌源分化。该目标将通过体外和体内研究实现。拟议的工作将打开调节HDAC6-C6ORF32调节相互作用以增强肌肉细胞融合的可能性，并以更广泛的范围使用C6ORF32作为肌肉修复的新目标。