(PQA2) MAMMALIAN REGENERATION, HIGH FAT DIETS, AND BREAST CANCER: A COMMON LINK?

(PQA2) 哺乳动物再生、高脂肪饮食和乳腺癌：共同的联系？

• 批准号: 8590786
• 负责人: Ellen s. Heber-Katz
• 金额: $ 37.75万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590786
• 关键词: Ablation; Address; Adipocytes; Adult; Autoimmunity; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Candidate Disease Gene; Cell Communication; Cell Proliferation; Cells; Chromosome Mapping; Chronic; Coculture Techniques; Complex; Diet; Endothelial Cells; Environment; Etiology; FABP4 gene; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Genes; Genetic; Goals; Growth; Human; Immune response; Immunocompetent; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Injection of therapeutic agent; LG/J Mouse; Laboratories; Lead; Link; MRL/MpJ Mouse; Malignant Neoplasms; Mammary Neoplasms; Measures; Modeling; Molecular; Mouse Strains; Mus; Natural regeneration; Neoplasm Metastasis; Newts; Obesity; PECAM1 gene; PTPRC gene; Parents; Phenotype; Population; Predisposition; Primary Neoplasm; Regulation; Resolution; Role; Site; Stromal Cells; Study Subject; System; Therapeutic; Tissues; Tumor Immunity; Tumor-Derived; Vascularization; Work; Wound Healing; angiogenesis; base; blastema; cancer cell; cancer therapy; cell growth; diet and cancer; feeding; fibroblast-activating factor; implantation; in vivo; inflammatory marker; innovation; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; oil red O; public health relevance; rapid growth; regenerative; response; tumor; tumor growth; tumor microenvironment; tumorigenesis

DESCRIPTION (provided by applicant): Obesity, often the result of a high fat diet, leads to chronic inflammation and stromal cell proliferation. In this application, we will address the issue of how a high fat diet leads to enhanced tumor cell growth and approach this from a previously unexplored direction. Examination of an adult mammalian regeneration model employing the MRL/MpJ mouse studied for its susceptibility to autoimmunity, obesity, and enhanced wound healing abilities, displays multiple phenotypes similar to the tumor microenvironment and has been the subject of study in the Heber-Katz laboratory for over a decade. The mapping of genes in this mouse has led to the identification of a novel gene signature defined by a small subset of genes which are regulated by a high fat diet in a sexually dimorphic fashion. The genes that constitute this so-called "high fat-selected regeneration-associated" or HFSRA gene signature are the basis of the proposed approach to defining the mechanistic basis for the association between a high fat diet and breast cancer. This approach is strongly supported by results demonstrating that these same genes are similarly expressed in human breast cancer-derived stromal cells. These studies will utilize the 4T1 orthotopic mouse breast cancer model in syngeneic BALB/c mice in vivo. In vitro studies will be carried out using 3D-culture systems relevant to the tumor microenvironment based on an understanding of the complexities of the tumor microenvironment and the host response to tumors, ranging from the role of stromal cells, inflammation and vascularization to tumor immunity, and is the focus of the Pur¿ laboratory. Working together as a team, the combined expertise of Drs. Heber-Katz and Pur¿ render the important but complex goals of this project eminently feasible.

描述（由应用提供）：肥胖通常是高脂饮食的结果，导致慢性感染和基质细胞增殖。在此应用程序中，我们将解决这个问题 关于高脂肪饮食如何导致肿瘤细胞生长增强，并从以前出乎意料的方向接近这一点。检查采用MRL/MPJ小鼠Studiod的成年哺乳动物再生模型的检查，以易于自身免疫性，肥胖和增强的伤口愈合能力，显示出与肿瘤微环境相似的多种表型，并且在十年来一直是Heber-Katz实验室中的研究主题。该小鼠中基因的映射导致鉴定了由一小部分基因定义的新型基因特征，这些基因以性二态性方式受到高脂饮食的调节。构成这种所谓的“高脂肪选择的再生相关”或HFSRA基因特征的基因是提出方法定义高脂肪饮食与乳腺癌之间关联的机械基础的基础。结果表明，这些相同基因在人类乳腺癌衍生的基质细胞中类似表达的结果得到了强烈支持。这些研究将利用体内的合成性BALB/C小鼠中的4T1原位小鼠乳腺癌模型。基于对肿瘤微环境的复杂性以及对肿瘤的宿主反应的理解，将使用与肿瘤微环境相关的3D培养系统进行体外研究，从基质细胞，感染和血管化的作用，肿瘤免疫学到肿瘤的作用，并且是pur pur puro的焦点。作为团队合作，DR的综合专业知识。 Heber-Katz和Pure`实现了该项目的重要但复杂的目标，这一点非常可行。