Sex specific epigenetic regulation of colon cancer metastasis

结肠癌转移的性别特异性表观遗传调控

基本信息

批准号：
10698017
负责人：
Y. Alan Wang
金额：
$ 39.56万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-06 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698017
关键词：
APC mutation Address Adherens Junction Animal Cancer Model Animal Model Binding Sites Biological Assay Biological Models Cancer Etiology Cell Line Cells Cessation of life ChIP-seq Clinical Trials Colorectal Cancer Combination immunotherapy Data Disease Progression Doxycycline Epigenetic Process Event Female Genes Genetic Genetically Engineered Mouse Goals Histones Human Immune In Vitro Institution Invaded KRAS oncogenesis KRAS2 gene KRASG12D Link Liver Luciferases MADH4 gene Maintenance Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Microsatellite Repeats Modeling Molecular Mus Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Oncogenes Other Genetics Patients Phenotype Play Prognosis Promoter Regions Proteins Reporter Role Sampling Sex Bias TP53 gene Testing Tumor Suppressor Genes Tumor-Derived Up-Regulation Y Chromosome cancer cell colon cancer cell line colon cancer metastasis colon cancer patients colorectal cancer metastasis colorectal cancer progression epigenetic regulation exome exome sequencing experimental study gain of function genome sequencing human female in vivo in vivo Model inhibitor knock-down loss of function male metastatic colorectal migration mouse model mutant novel novel therapeutic intervention overexpression preclinical study recruit sex sexual dimorphism siRNA delivery targeted agent therapeutic target transcriptome sequencing tumor microenvironment whole genome

项目摘要

Colorectal cancer (CRC) is the third leading cause of cancer death in US and is characterized by signature mutations of APC, p53, KRAS, SMAD4, among other genetic alterations. It is well established that male CRC patients have worse prognosis than that of female patients, but the underlying mechanism is largely undefined. Recent efforts in large scale whole genome and whole exome sequencing of metastatic CRC samples have not identified novel metastatic promoting genes suggesting metastatic progression may be largely regulated by epigenetic mechanisms. We have recently established an inducible oncogenic KRas metastatic CRC animal model and employing this model we have identified a male specific Y-chromosome residing gene- KDM5D, as a key regulator of CRC metastatic progression. This discovery is exciting as it connects sex biased CRC progression with an epigenetic regulator that is druggble. In this proposal, we will employ both in vitro and animal models to elucidate the function of KDM5D in CRC progression and define novel therapeutic approach targeting CRC metastasis. To achieve this goal, we propose the following specific aims. 1. Elucidate the role of KDM5D in CRC progression; 2. Define Kras mediated KDM5D upregulation in CRC and KDM5D downstream targets in promoting metastasis; 3. Mechanistic understanding of KDM5D promotion of metastasis in vivo.

结直肠癌（CRC）是美国癌症死亡的第三主要原因，其特征是签名 APC，p53，KRAS，SMAD4等的突变以及其他遗传改变。雄性CRC已经很好地确定患者的预后比女性患者的预后较差，但基本机制在很大程度上不确定。最新大规模的整个基因组和转移性CRC样品的整个外显子组测序尚未确定的新型转移性促进基因表明转移性进展可能在很大程度上受到表观遗传机制。我们最近建立了一种可诱导的致癌KRAS转移性CRC动物模型并采用此模型，我们已经确定了居住基因KDM5D的男性特异性Y-chromosoms CRC转移性进展的关键调节剂。这一发现令人兴奋，因为它连接了性偏见的CRC 具有药物的表观遗传调节剂的进展。在此提案中，我们将同时使用体外和动物阐明KDM5D在CRC进程中的功能并定义新的治疗方法靶向的模型 CRC转移。为了实现这一目标，我们提出以下特定目标。 1。阐明KDM5D的作用在CRC进展中； 2。定义KRAS介导的CRC和KDM5D下游目标中的KDM5D上调促进转移； 3。对kDM5D促进转移的机械理解。