Comparative Mechanisms of Cancer Chemoprevention

癌症化学预防的比较机制

• 批准号: 8464012
• 负责人: Roderick H Dashwood
• 金额: $ 150.3万
• 依托单位: OREGON 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: 2003-03-17 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464012
• 关键词: Accounting; Acetylation; Address; American Cancer Society; Apoptosis; Area; Biological Markers; Bronchi; Cancer Etiology; Cancer Intervention; Cell Cycle; Cell Cycle Arrest; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; DNA; DNA Methylation; DNA Sequence; Development; Diet; Dietary Factors; Dietary Indole; Dietary Isothiocyanate; Dietary Phytochemical; Disease; Epigenetic Process; Event; Food; Funding; Gender; Gene Expression; Gene Silencing; Genetic; Heart; Histone Deacetylase; Histone deacetylase inhibition; Histones; Human; Human Volunteers; Indole-3-Carbinol; Institutes; Lung Lymphoma; Lung Neoplasms; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medical Research; Methods; Methylation; Modification; Mutation; Pattern; Phase; Phosphorylation; Pre-Clinical Model; Prevention; Program Research Project Grants; Prostate Lymphoma; Research; Research Priority; Risk; Sulforaphane; United States National Institutes of Health; Update; Woman; Work; cancer cell; cancer chemoprevention; cancer prevention; cancer therapy; comparative; cruciferous vegetable; epigenetic marker; gene function; histone modification; in vivo; innovation; insight; leukemia; meetings; men; preclinical study; promoter; translational study; working group

DESCRIPTION (provided by applicant): The NIH Roadmap stipulates that epigenetics is a research priority. Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable, and dietary factors have been shown to "de-repress" epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. The overall long-term objectives of this P01 are to better understand the mechanisms by which beneficial epigenetic changes can be brought about by dietary agents, to identify and characterize epigenetic biomarkers that can be applied in the clinical setting, and to evaluate those biomarkers in preclinical and translational studies. With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the cell cycle and apoptosis. E. Ho will investigate "Chemoprevention of prostate cancer, HDAC inhibition, and DNA methylation" (Project 1), D.E. Williams will study "Transplacental chemoprevention of lung tumors and lymphomas" (Project 2), and R.H. Dashwood will examine "Chemoprevention of colon cancer, HDAC inhibition, and histone status" (Project 3). The overall significance of the work is that it seeks to provide new epigenetic insights into the prevention and treatment of colon, prostate, and lung cancer, as well as lymphoma, which are listed consistently among the top causes of cancer-related deaths in the US. This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet.

描述（由申请人提供）：NIH路线图规定表观遗传学是研究的优先事项。与与癌症相关的遗传变化不同，表观遗传变化可能会改变，饮食因素已显示出在癌细胞中“抑制”表观遗传基因的基因，从而触发细胞周期停滞和凋亡。该p01的总体长期目标是更好地了解饮食剂可以通过有益表观遗传学变化来确定和表征可以在临床环境中应用的表观遗传生物标志物的机制，并评估这些生物标志物在宝旋和翻译研究中。 With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA启动子甲基化状态，从而取消了调节细胞周期和凋亡的表观遗传沉默的基因。 E. Ho将研究“前列腺癌，HDAC抑制和DNA甲基化的化学预防”（项目1），D.E。威廉姆斯将研究“肺肿瘤和淋巴瘤的移植化学预防”（项目2），R.H. Dashwood将研究“结肠癌，HDAC抑制和组蛋白状态的化学预防”（项目3）。这项工作的总体意义在于，它试图为预防和治疗结肠，前列腺癌和肺癌以及淋巴瘤提供新的表观遗传学见解，这些见解始终被列为美国与癌症相关死亡的最大原因之一。该应用是创新的，并且及时弥合了表观遗传学和饮食的基本机制，临床前模型以及人类研究。