HILPDA and lipid metabolism in colorectal cancer

HILPDA 与结直肠癌中的脂质代谢

基本信息

批准号：
9000676
负责人：
Ioanna Papandreou
金额：
$ 7.7万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9000676
关键词：
APC gene Address Adipocytes Alleles Animal Model Animals Antibodies ApcMin/+ mice Appearance Area Azoxymethane Biochemical Biological Markers Biological Process Breeding Carcinogens Carcinoma Cells Clinical Clinical Research Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer Data Defect Development Disease Epithelial Cells Etiology Evolution Fibroblasts Firefly Luciferases Gene Expression Gene Proteins Genes Genetic Genetic Models Genetically Engineered Mouse Germ-Line Mutation Growth Health Human Hypoxia In Vitro Incidence Inflammation Inflammatory Inflammatory Infiltrate Intestinal Neoplasms Intestines Investigation KRAS2 gene Knock-out Length Lesion Light Link Lipid Biochemistry Lipid Mobilization Lipids Luc Gene Maintenance Malignant - descriptor Malignant Neoplasms Measures Metabolism Methods Modeling Morbidity - disease rate Mouse Protein Mouse Strains Mus Natural History Neoplasm Metastasis Normal tissue morphology Oncogenic Outcome Perfusion Physiological Physiology Predisposition Production Prognostic Factor Proteins Reagent Reporter Research Role Severities Signal Pathway Signal Transduction Signaling Molecule Sodium Dextran Sulfate Solid Neoplasm Specimen Staining method Stains Stimulus Stress Stromal Cells Structure TP53 gene Tertiary Protein Structure Testing Time Tissue Microarray Transcript Tumor Suppressor Proteins Tumor-Derived Variant adenoma adipocyte differentiation cancer type carcinogenesis cell type colon carcinogenesis data mining in vitro Model in vivo lipid biosynthesis lipid metabolism loss of function mortality mouse model overexpression perilipin prognostic significance programs protein expression protein function research study response therapeutic target tool tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a major cause of morbidity and mortality and is the result of well characterized genetic aberrations. However, there are additional factors that modulate malignant progression and response to therapy. A large number of solid tumors contain areas of hypoxia as a result of defective tumor vasculature and poor perfusion. Hypoxia activates adaptive gene expression programs, regulating crucial biological processes including proliferation, metabolism, and metastasis. The presence of hypoxia and associated features is an adverse prognostic factor in a number of cancer types, and strategies are being developed to either overcome hypoxia or target hypoxic physiology therapeutically. Hypoxia-Inducible Lipid Droplet Associated Protein (HILPDA) is a stress-induced gene, encoding for a protein shown to localize to lipid droplets. HILPDA transcripts are highly expressed in CRC specimens but the protein's functional importance or its relation to other clinical parameters is not known. We have generated a genetically engineered mouse model where the HILPDA gene was disrupted and was replaced by the firefly Luciferase gene. This knockout/reporter mouse strain will be used to investigate colorectal oncogenesis. We hypothesize that HILPDA is a positive modulator of malignant progression by impacting colonic epithelial and stromal cell responses to oncogenic signals. Additionally, an in vitro model of adipogenesis will be used to identify HILPDA protein functional domains. We propose these investigations in 3 specific aims: 1) We will investigate the role of HILPDA in vivo in two murine models of CRC: a) in inflammation-associated carcinogenesis induced by treatment with Azoxymethane and Dextran Sodium Sulfate and b) in the context of APC inactivation by breeding the APC Min nonsense allele into our strain. Tumor incidence and multiplicity will be kinetically measured and the spectrum of lesions will be pathologically evaluated in both models. 2) Protein expression of HILPDA will be validated as a biomarker of more aggressive disease in human CRC specimens. 3) We will also identify HILPDA functional domains that can rescue the adipogenesis defects and deficiency of lipid droplets of KO cells in vitro. These HILPDA domains will then be functionally tested in transplantable tumors. These studies will determine the significance of HILPDA in CRC malignant progression and generate reagents for the mechanistic analysis of HILPDA function.

描述（由申请人提供）：结直肠癌（CRC）是发病率和死亡率的主要原因，并且是明确表征的遗传畸变的结果。然而，还有其他因素可以调节恶性进展和治疗反应。由于肿瘤血管系统缺陷和灌注不良，大量实体瘤含有缺氧区域。缺氧激活适应性基因表达程序，调节关键的生物过程，包括增殖、代谢和转移。缺氧和相关特征的存在是许多癌症类型的不良预后因素，并且正在制定策略来克服缺氧或针对缺氧生理学进行治疗。缺氧诱导脂滴相关蛋白 (HILPDA) 是一种应激诱导基因，编码一种定位于脂滴的蛋白质。 HILPDA 转录本在 CRC 标本中高度表达，但该蛋白的功能重要性或其与其他临床参数的关系尚不清楚。我们构建了一个基因工程小鼠模型，其中 HILPDA 基因被破坏并被萤火虫荧光素酶基因取代。这种基因敲除/报告小鼠品系将用于研究结直肠肿瘤发生。我们假设 HILPDA 通过影响结肠上皮和基质细胞对致癌信号的反应而成为恶性进展的正调节剂。此外，脂肪生成的体外模型将用于鉴定 HILPDA 蛋白功能域。我们提出这些研究有 3 个具体目标：1) 我们将研究 HILPDA 在两种 CRC 小鼠模型中的体内作用：a) 在用氧化偶氮甲烷和右旋糖酐硫酸钠治疗诱导的炎症相关致癌作用中，b) 在通过将 APC Min 无义等位基因培育到我们的菌株中来使 APC 失活。在这两个模型中，将对肿瘤发生率和多重性进行动力学测量，并对病变范围进行病理学评估。 2) HILPDA 的蛋白表达将被验证为人类 CRC 标本中更具侵袭性疾病的生物标志物。 3）我们还将鉴定可以在体外挽救KO细胞的脂肪生成缺陷和脂滴缺陷的HILPDA功能域。然后，这些 HILPDA 结构域将在可移植肿瘤中进行功能测试。这些研究将确定 HILPDA 在 CRC 恶性进展中的重要性，并产生用于 HILPDA 功能机制分析的试剂。