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Role of Id1 in adiposity, energy balance and obesity associated liver tumorigenes

Id1 在肥胖、能量平衡和肥胖相关肝脏肿瘤发生中的作用

基本信息

批准号：
8887311
负责人：
Satyanarayana Ande
金额：
$ 8.99万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887311
关键词：
Ablation Adipose tissue Adult Adverse effects Age BAY 54-9085 BHLH Protein Blood Circulation Brown Fat Cancer Cell Growth Cancer Etiology Cell Line Cell Proliferation Cell physiology Cessation of life Chronic Hepatitis B DNA Binding Diet Drug Targeting Energy Metabolism Epidemiologic Studies FDA approved Fatty acid glycerol esters Gene Targeting Genes Goals Helix-Turn-Helix Motifs Hepatitis B Hepatitis C Hepatocyte Human In Vitro Infection Inflammatory Interleukin-6 Knockout Mice Liver Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Mediating Metabolic Diseases Metabolism Modeling Molecular Target Mus Obesity Obesity associated cancer Oncogenes Overweight Pathway interactions Primary carcinoma of the liver cells Proteins Regulation Research Research Personnel Risk Factors Role Sampling TNF gene Thermogenesis Transgenic Mice Transgenic Model Unresectable Work base cancer cell cancer initiation cancer risk cytokine differentiation protein 1 inhibitor energy balance genetic approach inhibitor/antagonist liver inflammation malignant stomach neoplasm mouse model novel overexpression prevent public health relevance transcription factor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Recent epidemiological studies revealed that obesity results in a substantial increase in cancer risk including HCC. Accordingly, it was described that obesity promotes liver inflammation and tumorigenesis in mice by enhancing circulating levels of inflammatory cytokines such as IL-6 and TNF¿. Therefore, in obesity associated cancers an ideal molecular target is the one whose inhibition should a) suppress cancer cell proliferation, and b) reduce body adiposity and circulating inflammatory cytokines. Id1 (inhibitor of DNA binding 1) is a helix-loop-helix (HLH) transcription factor that functions as a negative regulator f basic helix-loop-helix (bHLH) transcription factors. Id1 promotes cell proliferation and inhibits cellular differentiation. It was shown that Id1 is overexpressed in many human cancers including HCC, however, the specific role of Id1 in HCC initiation and progression is not known. Recently, I discovered that Id1 is highly expressed in adipose tissues, especially in brown adipose tissue (BAT), and Id1-deficiency in mice resulted in enhanced thermogenesis due to induced expression of PGC1¿ and UCP1, critical regulators of thermogenesis. These studies together suggest that Id1 functions as a critical regulator in two different cellular processes; cell proliferation and cellular metabolism. Taken together, I hypothesize that deletion of Id1 suppresses obesity associated HCC by two mechanisms: 1. Id1 is required for cancer cell proliferation, and deletion of Id1 suppresses liver tumor growth. 2. Deletion of Id1 enhances thermogenesis, reduces body adiposity and circulating inflammatory cytokines, therefore, prevents liver inflammation that contributes to liver tumor growth. The objective of this proposal is to investigate the specific role of Id1 in obesity associated liver tumorigenesis. In pursuit of this two specific aims are proposed. Aim 1: I will investigate the consequence of loss of Id1 in the regulation of PGC1¿ and UCP1 in BAT mediated thermogenesis. For this purpose, I generated Id1fl/fl conditional knockout mice and adipose tissue specific deletion of Id1 will be achieved by crossing with aP2Cre mice which will allow me to investigate the impact of loss of Id1 in the regulation of thermogenic pathway and body adiposity. Aim 2: The second aim will investigate the effect of loss and overexpression of Id1 in liver tumorigenesis, and identify potential cooperating partners of Id1 that are involved in HCC progression. For this purpose I will use Id1fl/flAlbCre mice, and generate a new transgenic model (Alb- Id1Tg) to evaluate the consequence of liver specific loss and overexpression of Id1 on HCC initiation and progression. In addition, by combined deletion of Id1 in adipose tissue and liver, and by utilizing high fat die (HFD) model of obesity, I will investigate if lack of Id1 prevents obesity associated HCC.

描述（由申请人提供）：肝细胞癌（HCC）是全球癌症死亡的主要原因之一。最近的流行病学研究表明，肥胖导致包括HCC在内的癌症风险大幅增加。因此，据描述，肥胖通过提高循环中的炎症细胞因子（如IL-6和TNF -）水平，促进小鼠的肝脏炎症和肿瘤发生。因此，在肥胖相关癌症中，理想的分子靶点是抑制a)抑制癌细胞增殖，b)降低体脂和循环炎性细胞因子的分子靶点。Id1 （inhibitor of DNA binding 1）是一种helix-loop-helix （HLH）转录因子，是碱性helix-loop-helix （bHLH）转录因子的负调控因子。Id1促进细胞增殖，抑制细胞分化。研究表明，Id1在包括HCC在内的许多人类癌症中过表达，然而，Id1在HCC发生和进展中的具体作用尚不清楚。最近，我发现Id1在脂肪组织中高表达，特别是在棕色脂肪组织（BAT）中，由于诱导了产热的关键调节因子PGC1¿和UCP1的表达，Id1缺乏的小鼠会导致产热增强。这些研究共同表明，Id1在两种不同的细胞过程中起关键调节作用；细胞增殖和细胞代谢。综上所述，我假设Id1的缺失通过两种机制抑制肥胖相关的HCC：Id1是癌细胞增殖所必需的，Id1的缺失会抑制肝脏肿瘤的生长。2. Id1的缺失增强了产热作用，减少了体脂和循环炎性细胞因子，从而阻止了导致肝脏肿瘤生长的肝脏炎症。本提案的目的是研究Id1在肥胖相关肝肿瘤发生中的具体作用。为了追求