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

描述(申请人提供)：肥胖，通常是高脂肪饮食的结果，导致慢性炎症和基质细胞增殖。在本应用程序中，我们将解决该问题 关于高脂肪饮食如何促进肿瘤细胞生长的研究，并从一个以前未知的方向进行研究。使用MRL/MPJ小鼠对成年哺乳动物再生模型进行检查，研究其对自身免疫、肥胖和增强伤口愈合能力的敏感性，显示出与肿瘤微环境相似的多种表型，十多年来一直是Heber-Katz实验室的研究对象。这只小鼠的基因图谱导致了一种新的基因签名的识别，该签名由一小部分基因定义，这些基因受高脂肪饮食以性别二态的方式调节。构成这种所谓的“高脂肪选择再生相关”或HFSRA基因签名的基因是所提出的定义高脂肪饮食与乳腺癌之间联系的机制基础的方法的基础。结果表明，这些相同的基因在人类乳腺癌来源的基质细胞中也有类似的表达，这一方法得到了强有力的支持。这些研究将利用同基因BALB/c小鼠体内的4T1原位小鼠乳腺癌模型。体外研究将在了解肿瘤微环境的复杂性和宿主对肿瘤的反应的基础上，使用与肿瘤微环境相关的3D培养系统进行，范围从基质细胞的作用、炎症和血管形成到肿瘤免疫，是PUR�实验室的重点。作为一个团队一起工作，Heber-Katz博士和Pur�博士的专业知识相结合，使这个项目的重要但复杂的目标变得非常可行。

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.