Insulin Receptor in Intestinal Growth, Tumorigenesis, Aging, and Obesity

胰岛素受体在肠道生长、肿瘤发生、衰老和肥胖中的作用

• 批准号: 8311497
• 负责人: Sarah Andres
• 金额: $ 2.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311497
• 关键词: Aberrant crypt foci; Affect; Affinity; Age; Aging; Apoptosis; Attenuated; Azoxymethane; B-insulin; Basic Science; Binding; Biological Markers; Cancer Cell Growth; Cancer Etiology; Cell Line; Cells; Cessation of life; Clinic; Clinical; Colonic Neoplasms; Colorectal Cancer; Complement; Conflict (Psychology); Data; Detection; Development; Diabetes Mellitus; Diagnosis; Diet; Differentiation Antigens; Disease; Epithelial; Epithelial Cells; Epithelium; Exons; Fatty Acids; Fatty acid glycerol esters; Fetal Development; Flow Cytometry; Gene Expression; Genes; Growth; Health Care Costs; Histology; Human; Hyperinsulinism; IGF2 gene; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Intestines; Knowledge; Lesion; Link; Lipids; Lipoproteins; Longevity; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Modeling; Molecular; Mus; Mutant Strains Mice; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligo-1,6-Glucosidase; Organoids; Outcome; Pathology; Pattern; Plasma; Premalignant; Prevention; Publishing; RNA Splicing; Receptor Signaling; Reporter; Reporter Genes; Risk; Risk Factors; Role; Signal Transduction; Small Interfering RNA; Staging; Stem cells; Sucrase; Testing; Translating; Variant; Villus; Work; absorption; adenoma; age related; aged; aging population; base; cancer risk; colorectal cancer prevention; feeding; human tissue; improved; insulin signaling; intestinal crypt; intestinal epithelium; lipid metabolism; mouse model; normal aging; overexpression; pandemic disease; progenitor; promoter; receptor; receptor sensitivity; response; tumor; tumor initiation; tumorigenesis; villin

DESCRIPTION (provided by applicant): Aging, obesity, and type 2 diabetes are major risk factors for colorectal cancer (CRC), which will cause close to 10% of cancer-related deaths in 2010. Identifying the molecular mediators that promote CRC and increase risk with aging, obesity, and diabetes is critical to improved detection, prevention, and treatment. Considerable evidence links elevated levels of plasma insulin to the increased CRC risk with aging, obesity, and diabetes, but the receptor mediating these effects of hyperinsulinemia is unknown. Insulin can bind to and activate both the insulin receptor (IR) and the related insulin-like growth factor-1 receptor (IGF1R). IGF1R is associated with growth and tumorigenesis in the intestinal epithelium, but the role of IR in the intestinal epithelium is not well defined. We have developed a mouse model with intestinal epithelial cell-specific deletion of IR to define the effects of IR loss during adaption to high-fat diet (HFD), over the normal course of aging, and during spontaneous and HFD-associated tumorigenesis. In addition, we have crossed the IR mutant mice to mice expressing EGFP under the promoter for the intestinal epithelial stem cell (IESC) biomarker Sox9. These mice will allow us to directly assess the role of IR in IESC. Our preliminary studies indicate that intestinal epithelial IR deletion decreases expression of differentiation marker sucrase-isomaltase, promotes growth of intestinal crypts in culture, and accelerates formation of aberrant crypt foci (ACF), the earliest precancerous lesions, in the azoxymethane (AOM) model of spontaneous tumorigenesis. This study uses two specific aims to test the central hypothesis that IR normally functions to promote differentiated function of intestinal epithelial cells and limit spontaneous or obesity-associated tumorigenesis. Aim 1 tests the hypothesis that deletion of IR expands IESC and impairs differentiation or differentiated function over the course of high-fat diet-induced obesity and normal aging. Aim 2 tests the hypothesis that intestinal epithelial IR deletion promotes spontaneous or obesity-associated colon tumors. The results of these studies will increase our fundamental understanding of IR in intestinal adaptation to aging and diet-induced obesity, as well as the role of IR in spontaneous and HFD-induced tumorigenesis. This knowledge is critical to improved CRC prevention, detection, and treatment in the face of an expanding aging population, the obesity pandemic, and the rising cost of healthcare.

描述（由申请人提供）：衰老、肥胖和2型糖尿病是结直肠癌（CRC）的主要危险因素，2010年结直肠癌将导致近10%的癌症相关死亡。确定促进CRC并增加衰老，肥胖和糖尿病风险的分子介质对于改善检测，预防和治疗至关重要。相当多的证据表明，血浆胰岛素水平升高与CRC风险增加以及衰老、肥胖和糖尿病有关，但介导高胰岛素血症这些效应的受体尚不清楚。胰岛素可以结合并激活胰岛素受体（IR）和相关的胰岛素样生长因子-1受体（IGF 1 R）。IGF 1 R与肠上皮细胞的生长和肿瘤发生有关，但IR在肠上皮细胞中的作用尚未明确。我们开发了一种肠上皮细胞特异性IR缺失的小鼠模型，以确定在适应高脂饮食（HFD）期间，在正常衰老过程中以及在自发和HFD相关肿瘤发生期间IR损失的影响。此外，我们已经将IR突变小鼠与在肠上皮干细胞（IESC）生物标志物Sox 9的启动子下表达EGFP的小鼠杂交。这些小鼠将使我们能够直接评估IR在IESC中的作用。我们的初步研究表明，肠上皮IR缺失降低分化标志物蔗糖酶-异麦芽糖酶的表达，促进培养中肠隐窝的生长，并加速形成异常隐窝病灶（ACF），最早的癌前病变，在氧化偶氮甲烷（AOM）模型的自发性肿瘤发生。本研究使用两个具体的目的来测试的中心假设，IR正常功能，以促进肠上皮细胞的分化功能，并限制自发或肥胖相关的肿瘤发生。目的1检验IR缺失在高脂饮食诱导的肥胖和正常衰老过程中扩大IESC并损害分化或分化功能的假设。目的2检验肠上皮IR缺失促进自发性或肥胖相关性结肠肿瘤的假设。这些研究的结果将增加我们对IR在肠道对衰老和饮食诱导的肥胖的适应中的基本理解，以及IR在自发性和HFD诱导的肿瘤发生中的作用。这些知识对于改善CRC的预防、检测和治疗至关重要，因为面对不断扩大的老龄化人口、肥胖流行病和不断上涨的医疗保健成本。