HDAC functions in skin development, renewal and disease

HDAC 在皮肤发育、更新和疾病中发挥作用

• 批准号: 9026566
• 负责人: Sarah E. Millar
• 金额: $ 34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026566
• 关键词: Acetylation; Affect; Basal cell carcinoma; Benefits and Risks; Binding; Binding Sites; Biochemical; Cell Proliferation; Cell Survival; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Complex; Data; Development; Disease; Embryo; Embryonic Development; Epidermis; Epithelial Cells; Epithelium; FOXP1 gene; Failure; Family member; Gene Expression; Gene Targeting; Genes; Genetic; Genomic approach; Genomics; Goals; HDAC1 gene; HDAC2 gene; HDAC3 gene; Hair follicle structure; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Homeostasis; Human; Individual; Left; Lysine; Maps; Mass Spectrum Analysis; Multiprotein Complexes; Mus; Mutation; NuRD complex; Nuclear Receptors; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Proliferating; Risk; Role; Site; Skin; Squamous cell carcinoma; Stem cells; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; base; chromatin modification; inhibitor/antagonist; interest; keratinocyte; member; mouse model; mutant; neoplastic cell; novel; postnatal; premature; progenitor; programs; promoter; research study; self-renewal; skin organogenesis; skin regeneration; stem; therapeutic target; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Project summary Embryonic development and postnatal renewal of the epidermis and hair follicles require coordinated changes in gene expression that are often dysregulated in tumorigenesis. Histone deacetylases (HDACs) provide global control of gene expression programs by repressive modification of chromatin, and form several classes, of which Class 1 members display the highest histone deacetylase activity. Of these, HDACs 1 and 2 associate with Mi2?, MTA-2 and MDB3 in the NuRD complex and with Sin3, SAP18 and SAP30 in the Sin3 complex, while HDAC3 complexes with N-CoR or SMRT. HDAC inhibitors (HDACi) are promising therapeutic agents for multiple types of tumor. However, while the functions and targets of individual HDACs vary widely, most HDACi broadly inhibit Class 1 HDACs, and their precise mechanisms of action are poorly understood. The goals of this proposal are to use genetic, biochemical, and global genomic approaches to delineate and compare the functions of HDAC1, HDAC2 and HDAC3 in the development and regeneration of skin epithelia, to identify transcription factors that target individual HDACs to specific sets of promoters in skin epithelial cells, and to determine the consequences of deletion of Hdac1, 2 or 3 for the initiation and progression of epidermal tumors. Data from these experiments will be critical for evaluating the potential risks and benefits of targeting individual HDACs in the epidermis and for developing more specific and effective therapeutics.

描述（由申请人提供）：表皮和毛囊的项目摘要的胚胎发育和产后更新需要基因表达的协调变化，而基因表达的变化通常在肿瘤发生中失调。组蛋白脱乙酰基酶（HDACS）通过抑制染色质的抑制性修饰，形成几类，其中1类成员显示最高的组蛋白脱乙酰基酶活性。其中，HDACS 1和2与NURD复合物中的MI2？，MTA-2和MDB3相关联，SIN3复合物中的SIN3，SAP18和SAP30与SIN3复合物中的SIN3，SAP18和SAP30相关，而HDAC3复合物与N-COR或SMRT相关。 HDAC抑制剂（HDACI）是多种类型肿瘤的有前途的治疗剂。但是，尽管单个HDAC的功能和目标差异很大，但大多数HDACI广泛抑制了1类HDAC，并且它们的精确作用机理知之甚少。该提案的目标是使用遗传，生化和全球基因组方法来描述和比较HDAC1，HDAC2和HDAC3在皮肤上皮elia的开发和再生中的功能，以确定针对单个HDAC的转录因子，以确定针对皮肤和启动子在皮肤上皮细胞和启动子的特定启动子的启动者的启动者的特定效果，并确定hH的启动者的特定启动子，并确定HER的启动者的效果。表皮肿瘤。这些实验的数据对于评估靶向表皮中各个HDAC的潜在风险和益处以及开发更具体和更有效的治疗剂至关重要。