Function of HDAC7 in Osteoblasts

HDAC7 在成骨细胞中的功能

• 批准号: 8094240
• 负责人: ERIC D JENSEN
• 金额: $ 11.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-20 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094240
• 关键词: Applications Grants; BMP2 gene; Biological; Biology; Bone Growth; Bone Regeneration; Cell Line; Cell Nucleus; Cells; Deacetylation; Dental; Development; Disease; Environment; Epitopes; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Histone Deacetylase; Injury; Knowledge; Lead; Lentivirus Vector; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Molecular; Nuclear; Nuclear Export; Orthopedics; Osteoblasts; Osteogenesis; Pathway interactions; Physiology; Proteins; Publishing; RNA Interference; Recruitment Activity; Regulation; Repression; Research; Role; Technical Expertise; Testing; Tooth structure; Transcription Repressor/Corepressor; Work; base; bone; bone healing; bone morphogenic protein; clinical application; craniofacial; gel electrophoresis; gene repression; improved; innovation; insight; interest; malformation; mutant; novel; novel therapeutics; osteoblast differentiation; osteogenic; overexpression; precursor cell; promoter; protein kinase D; public health relevance; research study; response; skeletal; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): Better therapies to promote bone growth and regeneration are needed for many craniofacial, dental and orthopedic conditions. To improve our ability to clinically manipulate the formation of bone by osteoblasts will require a deeper understanding of the molecular mechanisms that govern their physiology. I have identified histone deacetylase 7 (HDAC7) as an important regulator of osteoblast differentiation that has potential implications for the development of new bone restorative therapies. HDAC7 is a transcriptional repressor in osteoblasts. Suppression of HDAC7 expression accelerated BMP2-stimulated osteoblast differentiation, suggesting that HDAC7 negatively regulates osteoblast differentiation. Therefore, antagonism of HDAC7 function would be anticipated to elicit a bone-anabolic response. Treatment with osteoblast precursors with BMP2 leads to export of HDAC7 from the nucleus, presumably relieving target genes from its repressive effects. My central hypothesis is that HDAC7 is recruited to the promoter of genes required for osteoblast differentiation by Runx2 and other transcription factors, where it associates with other regulators to bring about transcriptional repression. I further hypothesize that nuclear export of HDAC7 is necessary to allow osteoblast gene expression and cellular differentiation. I have developed HDAC7-overexpressing osteoblast-like cells that will enable me to test these hypotheses by two specific aims: 1) Define the effects of overexpressed and constitutively-nuclear HDAC7 on osteoblasts; and 2) Identify HDAC7-associated proteins in osteoblasts. Completion of these aims will improve our understanding of HDAC7's role in bone physiology and as a possible therapeutic target and as a mediator of BMP2 in craniofacial, orthopedic and dental applications. PUBLIC HEALTH RELEVANCE: Improved therapies are needed to facilitate treatment of the diseases and injuries that involve damage or malformation to bone of the craniofacial region. My previous work suggests that Histone Deacetylase 7 (HDAC7) inhibits differentiation of osteoblasts and revealed that HDAC7 is a target of bone morphogenic protein 2, which is currently used clinically to stimulate localized bone growth. This grant proposal will determine the functional role of HDAC7 and identify novel factors that cooperate with HDAC7 during skeletal growth. These results are important steps towards development of new therapeutic strategies for promoting bone growth and healing.

描述（由申请人提供）：许多颅面、牙科和骨科疾病需要更好的治疗方法来促进骨生长和再生。为了提高我们在临床上操纵成骨细胞形成骨的能力，需要更深入地了解控制其生理学的分子机制。我已经确定组蛋白去乙酰化酶7（HDAC 7）作为成骨细胞分化的重要调节因子，对开发新的骨修复疗法具有潜在意义。HDAC 7是成骨细胞中的转录抑制因子。HDAC 7表达的抑制加速BMP 2刺激的成骨细胞分化，表明HDAC 7负调控成骨细胞分化。因此，预计HDAC 7功能的拮抗作用会引起骨合成代谢反应。用BMP 2处理成骨细胞前体导致HDAC 7从细胞核中输出，推测是解除了靶基因的抑制作用。我的中心假设是，HDAC 7被Runx 2和其他转录因子招募到成骨细胞分化所需基因的启动子，在那里它与其他调节因子相关联，导致转录抑制。我进一步假设HDAC 7的核输出对于成骨细胞基因表达和细胞分化是必要的。我已经开发了HDAC 7过表达的成骨细胞样细胞，这将使我能够通过两个特定的目标来测试这些假设：1）定义过表达和组成型核HDAC 7对成骨细胞的影响; 2）识别成骨细胞中的HDAC 7相关蛋白。这些目标的完成将提高我们对HDAC 7在骨生理学中的作用的理解，并作为可能的治疗靶点和作为BMP 2在颅面、整形外科和牙科应用中的介体。 公共卫生相关性：需要改进的疗法来促进涉及颅面区域的骨的损伤或畸形的疾病和损伤的治疗。我以前的工作表明，组蛋白脱乙酰酶7（HDAC 7）抑制成骨细胞的分化，并揭示HDAC 7是骨形态发生蛋白2的靶点，目前临床上用于刺激局部骨生长。这项拨款提案将确定HDAC 7的功能作用，并确定在骨骼生长过程中与HDAC 7合作的新因子。这些结果是发展促进骨生长和愈合的新治疗策略的重要步骤。