INHERITED AND SOMATIC ALTERATIONS OF THE TGF-B LIGAND AND RECEPTOR COMPLEX IN C..

C. TGF-B 配体和受体复合物的遗传性和体细胞改变

基本信息

批准号：
8704276
负责人：
CHRISTOPHER M WEGHORST
金额：
$ 73.14万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704276
关键词：
Address Affect Affinity Alanine Alcohols Alleles Appalachian Region Behavior Behavioral Binding Biological Biological Assay Biological Markers Biological Models Biopsy Blood Breast Breast Cancer Cell Bypass Cancer Etiology Cancer Patient Cell Cycle Deregulation Cell Proliferation Cell physiology Cell surface Cervical Cervix Neoplasms Cessation of life Characteristics Clinic Code Colon Carcinoma Colorectal Communities Complex DNA Data Death Rate Development Diagnosis Disease Dose Environmental Carcinogens Environmental Risk Factor Epithelial Cells Epstein-Barr Virus Infections Equilibrium Esophageal Event Exons Exposure to Frequencies Future General Population Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Growth Half-Life Head and Neck Neoplasms Head and neck structure Health Services Accessibility Health Status Heterozygote High Prevalence Human Human Herpesvirus 4 Human Papillomavirus Human papilloma virus infection Immune In Situ In Vitro Incidence Individual Inherited Intervention Lead Lesion Life Style Ligands Link Lung MAPK3 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Mediating Medical Messenger RNA Meta-Analysis MicroRNAs Modeling Molecular Mutation Neighborhoods Oncogenic Other Genetics Outcome Pancreas Pap smear Pathology Pathway interactions Patients Penetrance Peptide Signal Sequences Play Population Predisposition Prevalence Proteins Relative Risks Reporting Research Resource Sharing Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Secure Sex Behavior Signal Pathway Signal Transduction Site Smoking Social Conditions Social Network Socioeconomic Factors Somatic Mutation Specimen Stomach TGF-beta type I receptor TGFB1 gene TGFB2 gene TGFB3 gene TGFBR1 gene TGFBR2 gene Time Tissues Tobacco Tobacco use Training Transfection Transforming Growth Factor beta United States Variant Woman Work base behavior influence cancer cell cancer risk career development cell motility cohort community based participatory research design functional loss genetic variant health disparity high risk insight member mortality novel population health programs receptor screening social social health determinants social stress socioeconomics tumor

项目摘要

Invasive cervical cancer (ICC) is the most common cause of cancer death worldwide, and while decreasing in prevalence in the majority of the developed world, this disease continues to disproportionately affect certain populations in the United States (US). In particular, the rate of ICC incidence and mortality in Appalachian women is the highest in the US. While many risk factors are known to influence ICC development, little is known about the role of hereditary and genetic susceptibility factors. The transforming growth factor beta (TGF-B) is a universal critical regulator of various cellular functions, including cell proliferation, via its binding with a receptors complex on the cell surface. Cancer cells frequently avoid the inhibitory influence of TGF-B on cell proliferation via somatic inactivation of key components of the signaling pathway, including the ligand and receptor complex. Additionally, germline polymorphisms in the ligand and receptors have been associated with cancer development and increased cancer susceptibility. In this proposal, we hypothesize that the increased incidence of ICC observed in Appalachian women over their non-Appalachian counterparts is due in part to inherited and somatic alteration of the TGF-B ligand and receptor complex that can be further potentiated in association with various environmental, behavioral, and socioeconomic risk factors. Specifically, we will determine prevalence of inherited polymorphic and somatically acquired variants of key TGF-B pathway components in a large cohort of Appalachian ICC patients compared to healthy Appalachian women. Furthermore, we will determine whether these genetic alterations contribute individually or in combination with other known environmental (Human Papillomavirus, Epstein-Barr Virus), behavioral (smoking), and social (stress, social networks) risk factors, to the increased susceptibility of Appalachian women to ICC development.

浸润性宫颈癌 (ICC) 是全球癌症死亡的最常见原因，虽然在大多数发达国家，这种疾病的患病率有所下降，但这种疾病仍然对美国 (US) 的某些人群产生不成比例的影响。特别是阿巴拉契亚地区女性的 ICC 发病率和死亡率是美国最高的。虽然已知许多风险因素会影响 ICC 的发展，但人们对遗传和遗传易感因素的作用知之甚少。转化生长因子β (TGF-B) 是多种细胞功能的通用关键调节剂，包括细胞增殖，通过与细胞表面的受体复合物结合。癌细胞经常通过信号通路关键成分（包括配体和受体复合物）的体细胞失活来避免 TGF-B 对细胞增殖的抑制影响。此外，配体和受体的种系多态性与癌症发展和癌症易感性增加有关。在本提案中，我们假设阿巴拉契亚女性中观察到的 ICC 发病率高于非阿巴拉契亚女性，部分原因是 TGF-B 配体和受体复合物的遗传性和体细胞改变，这种改变可以与各种环境相关而进一步增强。、行为和社会经济风险因素。具体来说，我们将确定一大群阿巴拉契亚 ICC 患者与健康阿巴拉契亚女性相比，关键 TGF-B 通路成分的遗传多态性和体细胞获得性变异的患病率。此外，我们将确定这些基因改变是否单独或与其他已知的环境（人乳头瘤病毒、爱泼斯坦-巴尔病毒）、行为（吸烟）和社会（压力、社交网络）风险因素一起导致阿巴拉契亚山脉易感性增加女性到国际刑事法院发展。