The Role of Phosphatase of Regenerating Liver-3 in Alcohol-Associated Disease

再生肝磷酸酶 3 在酒精相关疾病中的作用

• 批准号: 8124323
• 负责人: Mark W. Zimmerman
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124323
• 关键词: Abbreviations; Adenomatous Polyposis Coli; Affect; Alcohol-Induced Disorders; Alcohols; Animal Model; Animals; Azoxymethane; Biological; Bromodeoxyuridine; Cell Proliferation; Colorectal Cancer; Disease; Drug Delivery Systems; Embryo; Endothelial Cells; Enzymes; Ethanol; Ethanol toxicity; Family; Frequencies; Gastrointestinal tract structure; Gene Targeting; Genes; Goals; Intestines; Knock-out; Knockout Mice; Lead; Life; Liver; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Natural regeneration; Organ; Phenotype; Phosphoric Monoester Hydrolases; Play; Process; Protein Tyrosine Phosphatase; Regulation; Reporting; Research; Research Proposals; Role; Sodium Dextran Sulfate; Tissues; alcohol abuse therapy; alcohol exposure; alcohol measurement; alcohol response; angiogenesis; cell motility; in vivo; innovation; intestinal epithelium; intraperitoneal; mouse model; novel; novel strategies; stem; therapeutic target; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this research proposal is to determine the role of Phosphatase of Regenerating Liver-3 (also known as PRL-3) in the biological response to alcohol exposure and toxicity. The PRL family of enzymes has become widely studied due to their potential roles in cancer and malignant disease, yet little is known and their function and regulation in vivo. Strong evidence indicates that PRL-3 is a mediator of several phenotypes elicited by ethanol exposure such as enhanced intestinal cell proliferation, angiogenesis, and cancers of the upper and lower digestive tract. These observations combined with our preliminary studies have indicated that there is a potential role for PRL-3 in mediating the phenotypes of alcohol exposure as well as alcohol-induced colorectal cancer. To study the role of PRL-3 in ethanol action, I have created a novel gene-targeted animal model can produce global and tissue-specific PRL-3 knockout mice. Using the knockout mouse model, the contribution of PRL-3 to alcohol-induced intestinal damage and alcohol-induced colorectal cancer will be assessed. These studies will ultimately lead to a better understanding of a gene potentially involved in the biological response to alcohol exposure as well as a potentially validating PRL-3 as a therapeutic target for the treatment of alcohol-induced colorectal cancer. PUBLIC HEALTH RELEVANCE: There is an enormous need to understand and treat the causes of alcohol-related diseases, particularly those that affect the gastrointestinal tract. Phosphatase of Regenerating Liver-3 is a gene associated with many of the phenotypes of alcohol exposure such as intestinal damage and alcohol-induced colorectal cancer. The studies proposed here represent an innovative approach to understanding a potentially important target for the treatment of alcohol-associated diseases.

描述(由申请人提供)：本研究提案的目标是确定再生肝磷酸酶-3(也称为PRL-3)在酒精暴露和毒性的生物反应中的作用。由于PRL家族在癌症和恶性疾病中的潜在作用，人们对其进行了广泛的研究，但对其在体内的功能和调节知之甚少。强有力的证据表明，PRL-3是酒精暴露引起的几种表型的媒介，如促进肠道细胞增殖、血管生成和上、下消化道癌症。这些观察结合我们的初步研究表明，在酒精暴露和酒精诱导的结直肠癌的表型中，PRL-3具有潜在的作用。为了研究PRL-3在酒精作用中的作用，我创造了一种新的基因靶向动物模型，可以产生全局和组织特异性的PRL-3基因敲除小鼠。利用基因敲除的小鼠模型，将评估PRL-3在酒精诱导的肠道损伤和酒精诱导的结直肠癌中的作用。这些研究最终将有助于更好地了解可能参与酒精暴露生物反应的基因，以及可能验证PRL-3作为治疗酒精诱导的结直肠癌的治疗靶点的可能性。 公共卫生相关性：非常需要了解和治疗与酒精有关的疾病的原因，特别是那些影响胃肠道的疾病。再生肝磷酸酶-3是一个与酒精暴露的许多表型相关的基因，如肠道损伤和酒精诱导的结直肠癌。这里提出的研究代表了一种创新的方法来理解酒精相关疾病治疗的潜在重要靶点。