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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大原因，其特征在于 APC、p53、KRAS、SMAD 4的突变以及其他遗传改变。众所周知，男性CRC 患者的预后比女性患者差，但潜在的机制在很大程度上是不确定的。最近在转移性CRC样本的大规模全基因组和全外显子组测序方面的努力尚未成功。鉴定的新的转移促进基因表明转移进展可能在很大程度上受表观遗传机制我们最近建立了一个诱导致癌KRas转移性CRC动物模型，模型，并利用该模型，我们已经确定了男性特异性Y染色体驻留基因-KDM 5D， CRC转移进展的关键调节因子。这一发现令人兴奋，因为它将性别偏见的CRC 一种可以用药的表观遗传调节器在这个建议中，我们将采用体外和动物模型，以阐明KDM 5D在CRC进展中的功能，并定义新的靶向治疗方法 CRC转移。为实现这一目标，我们提出以下具体目标。1.阐述KDM 5D的作用在CRC进展中; 2.确定CRC中Kras介导的KDM 5D上调和CRC中KDM 5D下游靶点促进转移; 3. KDM 5D促进体内转移的机制理解。