Integrating Epigenomic and Nuclear Receptor Signaling in Castrate Resistant Prostate Cancer

整合表观基因组和核受体信号在去势抵抗性前列腺癌中的应用

基本信息

批准号：
9103013
负责人：
Sarki A. Abdulkadir
金额：
$ 44.19万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103013
关键词：
Androgen Antagonists Androgens Animal Model Animals Biochemistry Biological Models Biology Breast Cancer Cell Cancer Etiology Cell Cycle Cell Proliferation Cell model Cell physiology Cells Cessation of life Complex Development Disease Drug Targeting Epigenetic Process Event Future Gene Activation Gene Expression Regulation Gene Targeting Genes Genetic Genome Glucocorticoid Receptor Goals Histone H3 Histones Hormone Receptor Hormones Human Human Characteristics In Vitro Knowledge Lead Lysine MLL gene Malignant Neoplasms Malignant neoplasm of prostate Methyltransferase Mitosis Modeling Modification Molecular Molecular Biology Nuclear Hormone Receptors Nuclear Receptors Nucleosomes Outcome Pathway interactions Patients Phase Phosphorylation Phosphotransferases Physiology Play Protein Kinase Proteins RNA Interference Receptor Signaling Recruitment Activity Refractory Regulation Research Research Personnel Resistance Role Signal Pathway Signal Transduction Therapeutic Thinking Threonine Tumorigenicity Vitamins Work androgenic base cohort epigenome epigenomics genetic signature genome-wide histone modification human disease in vivo killings member men neoplastic cell new therapeutic target novel novel therapeutics prostate cancer cell public health relevance receptor receptor function research study steroid hormone therapy resistant transcription factor

项目摘要

DESCRIPTION (provided by applicant): Androgen and its receptor AR, which is a member of the human nuclear receptor (NRs) superfamily, play critical roles in prostate cancer (PC) and castrate resistant prostate cancer (CRPC) that kills thousands of people world-wide. We posit that a better understanding of NR signaling pathway and its integration in epigenomic signaling are keys for development of future therapeutics of this deadly disease. The long term goal of our research is to discover novel components of NR function in transcriptional and epigenomic regulation with strong translational implications in human diseases. The protein kinase termed PKN1 plays a critical role in AR dependent gene regulation by establishing an epigenomic marking (histone H3 threonine 11 phosphorylation (H3T11P)) on nucleosomes at AR target genes. We hypothesize that the PKN1-H3T11P- WDR5 signaling module plays a previously unrealized and critical role in castrate resistant prostate cancer (CRPC). The goal of this present work is to perform in depth and integrative mechanistic, genome-wide, cellular and animal based studies to dissect the role of this newly discovered signaling module in AR function in CRPC. To achieve our research goals, we will utilize interdisciplinary knowledge and complementary expertise of the co-investigators spanning biochemistry, patho-physiology, genome biology, animal and cellular models of PC and molecular biology. In Specific Aims, we will examine in extensive molecular details the role of WDR5, and PKN1 in gene regulation, and CRPC-cell function in vitro and in vivo using cell and animal based models. We will also determine the gene-specific and genome-wide localization profiles of WDR5 and H3T11P in CRPC cells. Epigenomic markings and identification of their effector proteins in hormone action are new and rapidly evolving concepts and we believe our work lies at the limit of current knowledge of hormone signaling. Our findings will thus significantly advance the field by providing a better understanding of the role of epigenomic modifications and their effector proteins in nuclear receptor action and in human diseases including CRPC.

描述（由适用提供）：雄激素及其受体AR，它是人类核受体（NRS）超家族的成员，在前列腺癌（PC）和castrate抗性前列腺癌（CRPC）中起着关键作用，杀死了全球数千人。我们认为，更好地了解NR信号通路及其在表观基因组信号中的整合是开发这种致命疾病的未来治疗的关键。我们研究的长期目标是在转录和表观基因组调节中发现NR功能的新成分，对人类疾病具有很强的翻译意义。称为PKN1的蛋白激酶通过在AR靶基因的核小体上建立表观基因组标记（组蛋白H3苏氨酸11磷酸化（H3T11P），在AR依赖基因调节中起关键作用。我们假设PKN1-H3T11P-WDR5信号传导模块在castrate抗性前列腺癌（CRPC）中起先前未实现且至关重要的作用。目前的目标工作是在深度和综合机械，全基因组，基于细胞和动物的研究中执行，以剖析该新发现的信号传导模块在CRPC中的作用。为了实现我们的研究目标，我们将利用跨学科知识和跨越生物化学，病理生理学，基因组生物学，动物和PC和分子生物学细胞模型的共同评估者的完整专业知识。在特定目的中，我们将使用基于细胞和基于动物的模型在体外和体内进行广泛的分子细节研究WDR5和PKN1在基因调节中的作用，以及在体外和体内的CRPC细胞功能。我们还将确定CRPC细胞中WDR5和H3T11P的基因特异性和全基因组定位谱。表观基因组标记和对骑马作用中其效应蛋白的鉴定是新的且迅速发展的概念，我们认为我们的工作在于当前对骑马信号的知识的极限。因此，我们的发现将通过更好地理解表观基因组修饰及其效应蛋白在核受体作用以及包括CRPC在内的人类疾病中的作用来显着推进该领域。