Endothelial cell insulin and increased intestinal tumor formation in obesity

肥胖症中内皮细胞胰岛素与肠道肿瘤形成增加

基本信息

批准号：
8838069
负责人：
Christian Rask-Madsen
金额：
$ 18万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838069
关键词：
Abbreviations Adhesions Adult Advanced Malignant Neoplasm Animal Model Animals ApcMin/+ mice Area Back Binding Biology Blocking Antibodies Blood Vessels Breeding Cancer Control Cells Child Colon Carcinoma Data Development Diet Employee Strikes Endothelial Cells Endothelium Fatty acid glycerol esters Gene Deletion Genetic Recombination Genotype Growth Health Human Hyperinsulinism Immune Infiltration Insulin Insulin Receptor Insulin Resistance Integrin alpha4 Integrins Intervention Intestinal Neoplasms Intestines Knock-out Knockout Mice Knowledge Laboratories Leukocyte Rolling Leukocytes Malignant Neoplasms Measures Mediating Mesentery Metabolic Diseases Microscopy Mission Modeling Mus Mutant Strains Mice Mutation Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathway interactions Phenotype Play Population Positioning Attribute Prevalence Prevention Public Health Publishing Receptor Gene Research Risk Role Small Intestines Testing Tissues Transgenic Mice Transgenic Organisms Tumor Angiogenesis Tumor Burden Tumor Suppressor Genes United States Up-Regulation Vascular Cell Adhesion Molecule-1 Vascular Endothelium adenoma anticancer research base cancer cell cancer prevention cancer risk cancer type endothelial dysfunction feeding field study improved in vivo inhibitor/antagonist innovation insight insulin receptor substrate 1 protein insulin signaling mouse model novel overexpression prevent research study small molecule tumor tumor progression tumorigenesis vascular inflammation venule

项目摘要

DESCRIPTION (provided by applicant): More than one-third of the US population is now obese. Obesity is associated with colon cancer and other malignancies, and the increased prevalence of obesity threatens to set back advances made in cancer control. It has been proposed that this association could be due to growth- promoting effects of hyperinsulinemia. We propose an alternative in which hyperinsulinemia and cancer risk is both mediated by insulin resistance. We have previously published a striking phenotype of mice with endothelial cell knockout of the insulin receptor gene (Insr), an important aspect of endothelial dysfunction in obese humans. These animals have 4-fold increased leukocyte adhesion to endothelial cells because of endothelial cell upregulation of vascular cell adhesion molecule-1 (VCAM-1). Preliminary data from my lab now show that tumor-prone Apc (Min/+) mice with endothelial cell Insr knockout (IRKO/M mice) have increased tumor numbers in the small intestine compared with controls. They also have increased immune cell infiltration in small intestinal tissue. We therefore hypothesize that obesity-associated insulin resistance in endothelial cells promotes immune cell recruitment to the gut which in turn promote tumor development. With Aim 1, we will quantitate endothelial cell rolling and adhesion to endothelium in intestinal venules using in vivo microscopy. We will also determine whether treatment with an alpha4 integrin inhibitor, which blocks binding of leukocytes to VCAM-1, prevents the accelerated tumorigenesis in IRKO/M mice. With Aim 2, we will use Apc(Min/+) mice with transgenic overexpression of insulin receptor substrate-1 (IRS-1) in endothelial cells (Tg/M mice) or their controls (wt/M) after feeding them a high-fat or control diet. We will determine whether tumor burden and lekocyte rolling/adhesion in intestinal wall venules in vivo are improved in obese Tg/M mice compared to obese wt/M mice. The genetically modified mice described for both aims are available in our laboratory. This proposal is highly innovative because insulin resistance in cancer target tissues has not previously been thought to be the cause of the association between hyperinsulinemia and cancer risk in obesity. In addition, we introduce mouse tumor models with loss and gain of insulin signaling targeted to endothelial cells which allows us to study insulin resistance independent from hyperinsulinemia, thereby overcoming the problem that these two factors cannot be separated in humans or most animal models. The proposed research is significant because it will provide a target pathway for prevention of cancer in obesity.

描述（由申请人提供）：目前超过三分之一的美国人口患有肥胖症。肥胖与结肠癌和其他恶性肿瘤有关，肥胖患病率的增加可能会阻碍癌症控制方面取得的进展。有人提出这种关联可能是由于高胰岛素血症的生长促进作用。我们提出了一种替代方案，其中高胰岛素血症和癌症风险都是由胰岛素抵抗介导的。我们之前发表了内皮细胞胰岛素受体基因 (Insr) 敲除小鼠的惊人表型，胰岛素受体基因 (Insr) 是肥胖人类内皮功能障碍的一个重要方面。由于内皮细胞血管细胞粘附分子 1 (VCAM-1) 上调，这些动物的白细胞与内皮细胞的粘附增加了 4 倍。我实验室的初步数据显示，与对照组相比，内皮细胞 Insr 敲除的易发肿瘤 Apc (Min/+) 小鼠（IRKO/M 小鼠）的小肠肿瘤数量有所增加。它们还增加了小肠组织中的免疫细胞浸润。因此，我们假设内皮细胞中与肥胖相关的胰岛素抵抗促进免疫细胞向肠道募集，进而促进肿瘤的发展。通过目标 1，我们将使用以下方法定量肠小静脉中内皮细胞的滚动和内皮粘附：活体显微镜。我们还将确定使用 α4 整合素抑制剂（阻止白细胞与 VCAM-1 结合）进行治疗是否可以防止 IRKO/M 小鼠加速肿瘤发生。对于目标 2，我们将使用在内皮细胞（Tg/M 小鼠）或其对照（wt/M）中转基因过度表达胰岛素受体底物 1 (IRS-1) 的 Apc(Min/+) 小鼠，并在给它们喂食高剂量后使用它们。 - 脂肪或控制饮食。我们将确定与肥胖 wt/M 小鼠相比，肥胖 Tg/M 小鼠的体内肿瘤负荷和肠壁微静脉中的白细胞滚动/粘附是否有所改善。我们的实验室提供了针对这两个目标描述的转基因小鼠。该提议具有高度创新性，因为癌症靶组织中的胰岛素抵抗此前并未被认为是高胰岛素血症与肥胖癌症风险之间关联的原因。此外，我们引入了针对内皮细胞的胰岛素信号丢失和增加的小鼠肿瘤模型，这使我们能够研究独立于高胰岛素血症的胰岛素抵抗，从而克服了在人类或大多数动物模型中无法将这两个因素分开的问题。拟议的研究意义重大，因为它将提供预防肥胖癌症的目标途径。