Chemoprevention of colitis-associated colon cancer

结肠炎相关结肠癌的化学预防

基本信息

批准号：
7218103
负责人：
E. AUBREY THOMPSON
金额：
$ 7.38万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-04 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218103
关键词：
Accounting Affect American Animal Model Apoptotic Area Backcrossings Carboplatin/Cyclophosphamide Carcinogens Cations Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Trials Colectomy Colitis Colon Colon Carcinoma Corn Oil Data Development Diet Dietary Fats Doctor of Philosophy Enrollment Epithelial Cells Epithelium Etiology Event Fatty acid glycerol esters Fish Oils Genetic Genus Cola Hybrids Inbred C57BL Mice Incidence Inflammation Inflammatory Bowel Diseases Intestines Isoenzymes Kidney Knock-out Knockout Mice Laboratories Link Lipids Location Malignant - descriptor Malignant Neoplasms Mediating Mus Numbers Omega-3 Fatty Acids Operative Surgical Procedures PKC-betaII PPAR gamma Patients Peroxisome Proliferator-Activated Receptors Polyunsaturated Fatty Acids Predisposing Factor Proliferative Index Protocols documentation Publishing Risk Risk Factors Role Signal Transduction Staging Testing Tweens Ulcerative Colitis Work cyclophosphamide/doxorubicin/lomustine protocol indexing interest lifetime risk pre-clinical prevent prophylactic receptor research study size tumor

项目摘要

DESCRIPTION (provided by applicant): Ulcerative colitis is the single major risk factor for the development of colitis-associated colon cancer (CAC). Lifetime risk accruals for CAC may be as high as 43%, and CAC accounts for 1 in 6 deaths due to inflammatory bowel diseases. There is no known non-surgical chemopreventive strategy for CAC, although there is compelling evidence that diets that are rich in n-3 polyunsaturated fatty acids (n-3 PUFA, also known as (3 PUFA) suppress both colonic inflammation and carcinogen-induced colon cancer. These observations suggest that diets that are rich in n-3 PUFA may be effective means to prevent progression from inflammation to colon cancer, and one of our objectives is to test this hypothesis in a newly developed animal model of CAC. Our working hypothesis holds that the chemopreventive effects of n-3 PUFA are mediated, at least in part, by two lipid receptors: protein kinase C-beta II (PKC(ll) and peroxisome proliferator-activated receptor-gamma (PPAR(). Both of these entities have been shown to be important in the etiology of sporadic colon cancer, but their role in dietary lipid signaling in the colon has not been defined, and their role in CAC has not been investigated. We will utilize genetic knockout mice to determine if the tumor-suppressive effects of n-3 PUFA are dependent upon the expression of PKCpll or PPAR( in the colonic epithelium. Completion of these experiments will provide pre-clinical proof-of-principle for the use of dietary lipids in chemoprevention of CAC and will define the biologically plausible mechanisms that may account for alteration of CAC risk by essential dietary lipids. Confirmation of our hypotheses will provide essential pre-clinical proof-of-principle in support of clinical trials to determine if dietary n-3 PUFA prevents progression from colonic inflammation to CAC, will identify the role of PKC(ll and PPAR( in CAC, and may ultimately provide an alternative means of chemoprevention to patients who presently have no alternative to colectomy.

描述（由申请人提供）：溃疡性结肠炎是结肠炎相关结肠癌（CAC）发展的单一主要危险因素。 CAC的终生风险应计可能高达43％，而CAC由于炎症性肠道疾病而造成6分之1。尽管有令人信服的证据表明，富含N-3多不饱和脂肪酸的饮食（N-3 PUFA，也称为（3 PUFA）也抑制了结肠炎症和致癌物诱导的富含N-3的多不饱和脂肪酸（N-3 PUFA），但没有已知的非手术化学预防策略，尽管有令人信服的证据表明。结肠癌。这些观察结果表明，富含N-3 PUFA的饮食可能是防止炎症发展为结肠癌的有效手段，而我们的目标之一是在新开发的CAC模型中检验这一假设假设认为，N-3 PUFA的化学预防作用至少部分是由两个脂质受体介导的：蛋白激酶C-beta II（PKC（LL）和过氧化物酶体增殖物激活的受体 - Gamma（PPAR（PPAR（）。这些实体在零星结肠癌的病因中很重要，但是尚未定义它们在饮食中的脂质信号传导中的作用，并且它们在CAC中的作用尚未研究。 N-3 PUFA的肿瘤抑制作用取决于PKCPLL或PPAR的表达（在结肠上皮中。这些实验的完成将为临床前原则证明使用饮食脂质在CAC化学预防中，并将定义生物学上合理的机制，这些机制可能会通过必需的饮食脂质来解释CAC风险的改变。确认我们的假设将提供基本的临床前原则证明在支持临床试验中，以确定饮食中的N-3 PUFA是否可以防止从结肠炎症到CAC的发展，将确定PKC（LL和PPAR（CAC，在CAC，在CAC，在CAC中，在CAC，在CAC，在CAC中，在CAC，在CAC，在CAC中，在CAC，IN CAC，in in CAC，in in CAC，IN in CAC，in in CAC，IN in CAC，in IN CAC）并最终可能会为目前无法替代结肠切除术的患者提供化学预防的替代方法。