Analysis of a Novel Homeobox gene in CV Development

CV 发育中的新型同源盒基因分析

• 批准号: 7781354
• 负责人: Jonathan A. Epstein
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781354
• 关键词: Accounting; Adrenergic beta-Agonists; Adult; Affect; Alleles; Animal Model; Animals; Biochemical; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cells; Chemicals; Clinical; Clinical Treatment; Clinical Trials; Complex; Congenital Heart Defects; Congestive Heart Failure; Data; Development; Embryo; Embryonic Development; Embryonic Heart; Enzymes; Funding; Gene Targeting; Genes; Genetic; Glycogen (Starch) Synthase; Growth; HDAC2 gene; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Homeobox Genes; Homeodomain Proteins; Human; Humulus; Hypertrophy; Incidence; Inositol; Laboratories; Learning; Malignant Neoplasms; Modeling; Molecular; Molecular Target; Mus; Mutation; Myocardium; Organ; PDPK1 gene; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Play; Polyphosphates; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Recruitment Activity; Regulation; Research Infrastructure; Resistance; Role; Stress; Stretching; Structure; System; Testing; Tissues; United States; Work; cancer therapy; cardiogenesis; design; disability; disease diagnosis; driving force; fetal; gain of function; homeodomain; human disease; loss of function; mouse model; new therapeutic target; novel; novel therapeutics; programs; public health relevance; research study; therapeutic target

DESCRIPTION (provided by applicant): This is a revised (A1) competitive renewal application for an R01 initially focused on the role of a novel homeodomain protein called Hop that we discovered in the embryonic heart. We have found that Hop loss of function results in a developmental cardiac defect and that over-expression results in cardiac hypertrophy. Hop can function at the molecular level as a transcriptional co-repressor by recruiting class I HDACs. This finding led us to test the effects of HDAC inhibitors and we have found that these agents can block cardiac hypertrophy induced by Hop over-expression and also hypertrophy resulting from other stresses including beta-adrenergic agonists and stretch. Therefore, we have sought the specific class I HDAC(s) that account for these effects, and we have identified high levels of HDAC2 in the developing and adult heart. HDAC2 loss of function results in mice that are resistant to Hop- induced cardiac hypertrophy and to hypertrophy induced by beta-adrenergic agonists. We have shown that resistance to hypertrophy in these models is caused by constitutive activation of GSK3-beta, since antagonists of GSK3-beta restore the ability to hypertrophy on HDAC2 null animals. Our data indicates that HDAC2 affects the AKT-GSK3-beta pathway by directly repressing a novel inositol polyphosphate phosphatase called INPP5F, which functions to degrade PIP3 and thus affects the AKT cascade. These findings have direct clinical and translational implications since phosphatases are excellent drugable targets for the treatment of cardiovascular disease and because HDAC inhibitors are already in clinical trials for the treatment of cancer and could be readily adapted for use in the cardiac arena. Therefore, we will pursue these observations by: 1) Developing a floxed allele of HDAC2 in order to perform tissue and temporal specific deletion and to determine the effects of HDAC2 loss of function on regression of pre-established hypertrophy; 2) Elucidation of the genetic and biochemical interaction between Hop and HDAC2, and; 3) Examination of the function of INPP5F through gain and loss of function approaches in cells and in mice. These experiments offer strong prospects for developing new therapeutic avenues and paradigms for the treatment of cardiac hypertrophy and heart failure, with implications for the more general fields of cellular and organ growth regulation. PUBLIC HEALTH RELEVANCE: This project focuses on the causes of congestive heart failure, and on finding new therapeutic targets. Heart failure is a leading cause of death and disability in the United States, and the incidence is rising. We have found that HDAC inhibitors, which are drugs currently in clinical trials for cancer therapy, have beneficial effects in terms of heart failure prevention in animal models. This project explores the possibility that an enzyme called HDAC2, expressed in the heart, is the molecular target for HDAC inhibitors, and that it functions by regulating a novel phosphatase in the heart called INPP5F. We hope to determine if HDAC2 and INPP5F represent new targets for the development of specific therapies for heart disease.

描述（由申请人提供）：这是R 01的修订（A1）竞争性更新申请，最初专注于我们在胚胎心脏中发现的称为Hop的新型同源结构域蛋白的作用。我们已经发现，Hop功能丧失导致发育性心脏缺陷，并且过度表达导致心脏肥大。啤酒花可以通过募集I类HDAC在分子水平上作为转录共阻遏物发挥作用。这一发现使我们测试了HDAC抑制剂的作用，并且我们发现这些药物可以阻断由Hop过表达诱导的心脏肥大以及由其他应激（包括β-肾上腺素能激动剂和拉伸）引起的肥大。因此，我们已经寻找了导致这些效应的特定I类HDAC，并且我们已经在发育和成人心脏中鉴定了高水平的HDAC 2。HDAC 2功能丧失导致对啤酒花诱导的心脏肥大和对β-肾上腺素能激动剂诱导的肥大具有抗性的小鼠。我们已经表明，在这些模型中对肥大的抵抗是由GSK 3-β的组成性激活引起的，因为GSK 3-β的拮抗剂恢复了HDAC 2缺失动物的肥大能力。我们的数据表明，HDAC 2通过直接抑制一种称为INPP 5 F的新型肌醇多磷酸磷酸酶来影响AKT-GSK 3-β途径，INPP 5 F的功能是降解PIP 3，从而影响AKT级联反应。这些发现具有直接的临床和转化意义，因为磷酸酶是治疗心血管疾病的极好的药物靶标，并且因为HDAC抑制剂已经在用于治疗癌症的临床试验中，并且可以容易地适用于心脏竞技场。因此，我们将通过以下方式进行这些观察：1）开发HDAC 2的floxed等位基因，以进行组织和时间特异性缺失，并确定HDAC 2功能丧失对预先建立的肥大消退的影响; 2）阐明Hop和HDAC 2之间的遗传和生物化学相互作用; 3）在细胞和小鼠中通过功能获得和丧失方法检查INPP 5 F的功能。这些实验为开发新的治疗途径和治疗心脏肥大和心力衰竭的范例提供了强大的前景，并对细胞和器官生长调节的更广泛领域产生了影响。 公共卫生相关性：该项目侧重于充血性心力衰竭的原因，并寻找新的治疗靶点。心力衰竭是美国死亡和残疾的主要原因，并且发病率正在上升。我们发现HDAC抑制剂（目前正在进行癌症治疗临床试验的药物）在动物模型中预防心力衰竭方面具有有益作用。该项目探索了一种在心脏中表达的称为HDAC 2的酶是HDAC抑制剂的分子靶点的可能性，并且它通过调节心脏中称为INPP 5 F的新型磷酸酶发挥作用。我们希望确定HDAC 2和INPP 5 F是否代表了开发心脏病特异性疗法的新靶点。