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

• 批准号: 8305784
• 负责人: CHRISTOPHER M WEGHORST
• 金额: $ 81.01万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8305784
• 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; Screening procedure; 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; social; social health determinants; social stress; socioeconomics; tumor

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的患病率下降，但这种疾病继续不成比例地影响美国（US）的某些人群。特别是，阿巴拉契亚妇女的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，但对遗传和遗传易感性因素的作用知之甚少。转化生长因子β（TGF-β）是通过其与细胞表面上的受体复合物结合的各种细胞功能（包括细胞增殖）的通用关键调节剂。癌细胞通常通过信号传导途径的关键组分（包括配体和受体复合物）的体细胞失活来避免TGF-β对细胞增殖的抑制作用。此外，配体和受体的生殖系多态性与癌症发展和癌症易感性增加有关。在这项提案中，我们假设，在阿巴拉契亚妇女中观察到的ICC发病率增加，部分原因是由于遗传和TGF-B配体和受体复合物的体细胞改变，这种改变可以进一步增强与各种环境，行为和社会经济风险因素的关系。具体来说，我们将确定遗传多态性和体细胞获得的关键TGF-β通路的组成部分在一个大型队列的阿巴拉契亚ICC患者与健康的阿巴拉契亚妇女相比，变异的患病率。此外，我们将确定这些遗传变异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）风险因素相结合，导致阿巴拉契亚妇女对ICC的易感性增加 发展