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：
8302345
负责人：
EMANUELA GUSSONI
金额：
$ 39.15万
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/8302345
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.

描述（由申请人提供）：骨骼肌由成肌细胞融合形成的多核合胞体组成。通过微阵列研究，发现在人成肌细胞融合早期，当肌管包含 2-5 个肌核时，C6ORF32 的表达上调（Cerletti 等，2006）。 C6ORF32 表达的下调会由于肌细胞生成素表达显着降低而导致成肌细胞融合受阻（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结构域，即假定的 HDAC 结合结构域。研究发现，C6ORF32 与 HDAC6 结合，HDAC6 是一种 IIb 类 HDAC，因其促进细胞运动的功能而闻名。假设HDAC6和C6ORF32在功能上相连，并且HDAC6和C6ORF32之间的相互作用通过降低HDAC6的去乙酰化活性来正向调节肌原性分化。将通过以下具体目标在体外和体内研究骨骼肌中 HDAC6 和 C6ORF32 之间的调控联系： 1）定义 C6ORF32 与 HDAC6 的关键结合区域，并证明这两种蛋白的结合发生在体内； 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) 确定体内 C6ORF32 表达的消除是否会通过影响 HDAC6 功能而导致肌肉发育、功能和再生缺陷。这些研究将为了解未来针对 C6ORF32 和 HDAC6 之间的调节相互作用的药物疗法是否能够增强肌源性修复奠定基础。