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

描述（由申请人提供）：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。在本申请中，我们将解决这个问题 高脂肪饮食如何导致肿瘤细胞生长增强，并从以前未探索的方向着手。采用MRL/MpJ小鼠研究其对自身免疫、肥胖和增强的伤口愈合能力的易感性，对成年哺乳动物再生模型进行检查，显示出与肿瘤微环境相似的多种表型，并且十多年来一直是Heber-Katz实验室的研究主题。在这只小鼠中的基因作图导致了一种新的基因签名的鉴定，该基因签名由一小部分基因定义，这些基因以性二态的方式受高脂肪饮食的调控。构成这种所谓的“高脂肪选择性再生相关”或HFSRA基因签名的基因是所提出的方法的基础，该方法用于定义高脂肪饮食与乳腺癌之间关联的机制基础。这种方法得到了结果的有力支持，这些结果表明，这些相同的基因在人乳腺癌源性基质细胞中表达相似。这些研究将利用同基因BALB/c小鼠体内的4 T1原位小鼠乳腺癌模型。基于对肿瘤微环境复杂性和宿主对肿瘤反应的理解，将使用与肿瘤微环境相关的3D培养系统进行体外研究，范围从基质细胞的作用，炎症和血管化到肿瘤免疫，这是Pur实验室的重点。Heber-Katz博士和Pur <$博士作为一个团队一起工作，他们的专业知识使这个项目的重要但复杂的目标非常可行。

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.