Gastrins and Receptors in Colon Carcinogenesis

胃泌素和受体在结肠癌发生中的作用

基本信息

批准号：
7239556
负责人：
Pomila Singh
金额：
$ 28.67万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
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：
2003-07-10 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7239556
关键词：
Affect Affinity Animal Model Apoptosis Apoptotic Azoxymethane Binding Biological Blood Circulation CCKBR gene Cancer Etiology Cancerous Carcinogens Cells Cholecystokinin Cholecystokinin B Receptor Clinical Management Colon Carcinoma Colorectal Colorectal Cancer Diagnosis Dose Epithelial Epithelial Cells Epithelium Event Funding Future Gastrins Glucose Hand Injection of therapeutic agent Insulin Interleukin-2 Intestines Knockout Mice Laboratories Lesion Mediating Modeling Mucous Membrane Mus Mutant Strains Mice Pathology Patients Peptides Physiological Play Process Relative (related person)Reporting Research Personnel Risk Risk Factors Role Serum Testing Transgenic Mice Wild Type Mouse autocrine base cancer cell chemical carcinogen colon carcinogenesis feeding mortality mouse model mutant mouse model neoplastic novel outcome forecast progastrin programs protective effect receptor response tool

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer represents one of the leading causes of cancer-related mortality in the U.S. Hyperproliferation of colonic epithelium is now recognized as a risk factor for colorectal cancer. Factors that increase proliferation of colonic epithelium are believed to play a role in colon carcinogenesis. We now know that fully processed amidated gastrins (G17) and unprocessed non-amidated gastrins (gly-gastrin and progastrin, PG) are mitogenic for normal and cancerous intestinal cells. Our recent studies with mutant mice that over-express either PG or G17 or lack the functional gastrin gene (GAS-KO), suggest the novel possibility that PG is a co-carcinogen, while amidated gastrins inhibit rather than stimulate colon carcinogenesis. Differential effects of amidated (G17) vs non-amidated (PG) gastrins on colon carcinogenesis is a novel finding that will be further investigated in this application. The major hypothesis of this proposal is that PG increases the risk while G17 decreases the risk of colon carcinogenesis in response to chemical carcinogens. In Aim 1 we will confirm if PG is equally co-carcinogenic at physiological concentrations using more appropriate mutant mouse models. Possible dose-dependent effects of PG on colon carcinogenesis will be examined by treating GAS-KO mice with increasing concentrations of PG. In Aim 2 we will investigate the novel possibility that G17 reduces the risk of colon carcinogenesis, by either using mutant mouse models that over-express G17, treating GAS-KO mice and their wild type (WT) littermates with increasing concentrations of G17, or reducing endogenous levels of gastrins in WT mice. In Aim 3 we will investigate a role, if any, of gastrin receptor subtypes in mediating differential effects of PG vs G17. We recently reported a novel finding that PG may function as an anti-apoptotic factor for colon cancer cells and intestinal epithelial cells. In Aim 4, we will examine relative effects of PG vs G17 on apoptotic potential of colonic mucosal cells, that may help to explain differential effects between the two peptides. Results of the studies in the four Aims will allow us to confirm our novel hypotheses, and provide important mechanistic clues that will form the basis of studies in future funding periods. These results are expected to impact diagnosis, prognosis and clinical management of patients with colon cancer.

描述（由申请人提供）：结直肠癌是美国癌症相关死亡的主要原因之一。结肠上皮过度增殖现在被认为是结直肠癌的危险因素。据信，增加结肠上皮增殖的因素在结肠癌发生中发挥作用。我们现在知道，完全加工的酰胺化胃泌素 (G17) 和未加工的非酰胺化胃泌素（甘氨酸胃泌素和前胃泌素，PG）对正常和癌性肠道细胞具有促有丝分裂作用。我们最近对过度表达 PG 或 G17 或缺乏功能性胃泌素基因 (GAS-KO) 的突变小鼠进行的研究表明，PG 是一种共同致癌物，而酰胺化胃泌素则抑制而不是刺激结肠癌的发生。酰胺化 (G17) 与非酰胺化 (PG) 胃泌素对结肠癌发生的不同影响是一项新发现，将在本申请中进一步研究。该提案的主要假设是，PG 会增加化学致癌物导致结肠癌的风险，而 G17 则会降低结肠癌的风险。在目标 1 中，我们将使用更合适的突变小鼠模型来确认 PG 在生理浓度下是否同样具有共同致癌性。通过用增加浓度的 PG 治疗 GAS-KO 小鼠，将检查 PG 对结肠癌发生可能存在的剂量依赖性影响。在目标 2 中，我们将研究 G17 降低结肠癌发生风险的新可能性，方法是使用过度表达 G17 的突变小鼠模型，用增加浓度的 G17 治疗 GAS-KO 小鼠及其野生型 (WT) 同窝小鼠，或者降低 WT 小鼠胃泌素的内源水平。在目标 3 中，我们将研究胃泌素受体亚型在介导 PG 与 G17 差异效应中的作用（如果有的话）。我们最近报道了一项新发现，即 PG 可能作为结肠癌细胞和肠上皮细胞的抗凋亡因子。在目标 4 中，我们将检查 PG 与 G17 对结肠粘膜细胞凋亡潜力的相对影响，这可能有助于解释两种肽之间的差异效应。四个目标的研究结果将使我们能够证实我们的新假设，并提供重要的机制线索，这些线索将构成未来资助期间的研究基础。这些结果预计将影响结肠癌患者的诊断、预后和临床管理。