role of adipokines in colon epithelial cell homeostasis

描述（由申请人提供）： 在过去的20年里，肥胖症在美国以流行病的速度上升。预计随着肥胖的增加，结肠癌病例将增加;因此，关于肥胖如何增加结肠癌风险的研究非常及时，重要，并将影响后代。脂肪组织分泌激素和细胞因子（脂肪因子），可能在与肥胖和随后的结肠癌风险相关的全身炎症状态的发展中发挥作用。瘦素、白细胞介素-6（IL-6）和脂联素是可能在肥胖相关的癌症进展中起直接作用的三种这样的脂肪因子。虽然这些激素/细胞因子在稳态浓度下对正常细胞功能至关重要，但当水平从正常改变时（如肥胖），它们可能是病理性的。炎症相关性结肠癌是炎症性肠病中众所周知的临床现象，其中炎症刺激促进起始肿瘤细胞的存活和增殖。我们假设脂肪因子的不平衡是癌前细胞的关键炎症促进信号。有很强的生物学证据，流行病学证据支持，脂肪因子的失衡与肥胖相关的结肠癌有因果关系。然而，其机制尚不清楚。在我们对肥胖和结肠癌风险之间的相关性的机械理解中存在一个关键的差距。因此，本研究的长期目标是了解肥胖相关的脂肪因子系统性升高如何增加结肠癌风险。了解这些早期信号将导致肥胖相关结肠癌风险的癌症预防目标。本申请通过临床前建模研究了瘦素在癌前而非正常结肠上皮细胞中激活的差异细胞信号传导和蛋白酶机制。结肠癌的肿瘤性转化已得到很好的表征。我们将利用与转化范例一致的正常和癌前结肠上皮细胞，以两个具体目标来解决本申请的中心假设; 1）鉴定差异转录因子，其是导致瘦素诱导的细胞凋亡的原因。（和脂联素阻断）癌前结肠上皮细胞中IL-6信号传导增殖2）鉴定负责瘦素-诱导肿瘤前和正常结肠上皮细胞之间可溶性白细胞介素-6受体的差异脱落。预计在确定肥胖诱导的结肠癌促进的这种生物学机制后，靶向这种机制可能成为可能。本申请中的研究与公共卫生相关，因为了解肥胖相关因素的血液水平升高如何导致癌症的发展对结肠癌预防目标至关重要。作为这些研究的结果，这项研究确定的一种新机制也可能导致潜在治疗靶点的开发，以帮助预防和/或治疗肥胖相关的结肠癌风险。

DESCRIPTION (provided by applicant): During the past 20 years, obesity has risen at an epidemic rate in the United States. It is anticipated that with increased obesity colon cancer cases will increase; therefore, research regarding how obesity increases the risk of colon cancer is extremely timely, important and will affect upcoming generations. Adipose tissue secretes hormones and cytokines (adipokines) that may play a role in the development of the systemic inflammatory state associated with obesity and subsequent colon cancer risk. Leptin, interleukin-6 (IL-6) and adiponectin are three such adipokines that may a play direct role in obesity- associated cancer progression. While these hormones/cytokines are critical to normal cellular functioning at homeostatic concentrations, when levels are altered from normal (as in obesity) they may be pathologic. Inflammation-associated colon cancer is a well known clinical phenomenon in inflammatory bowel disease where inflammatory stimuli promote survival and proliferation of initiated neoplastic cells. We hypothesize that an imbalance in adipokines is a key inflammatory promotional signal for preneoplastic cells. There is strong biological plausibility, supported by epidemiologic evidence, that an imbalance in adipokines is causally related to obesity-associated colon cancer. However, the mechanism is not understood. A critical gap exists in our mechanistic understanding of the correlation between obesity and colon cancer risk. As such, the long-term goal of this research is to understand how obesity-associated systemic elevation of adipokines increases colon cancer risk. Understanding these early signals will lead to cancer prevention targets for obesity-associated colon cancer risk. This application investigates the differential cell signaling and proteinase mechanisms activated by leptin in preneoplastic but not normal colon epithelial cells through preclinical modeling. The neoplastic transformation of colon cancer is well characterized. We will utilize normal and preneoplastic colonic epithelial cells consistent with the transformation paradigm to address the central hypothesis of this application in two specific aims; 1) identify differential transcription factors that are causally responsible for leptin-induced (and adiponectin blocked) IL-6 signaling proliferation in preneoplastic colon epithelial cells 2) identify proteinases responsible for leptin-induced differential shedding of the soluble interleukin-6 receptor between preneoplastic and normal colonic epithelial cells. It is anticipated that upon identification of this biological mechanism of obesity-induced colon cancer promotion, it may become possible to target this mechanism. The research in this application is relevant to public health because it is critical to colon cancer prevention targets to understand how elevated blood levels of obesity-associated factors may lead to the development of cancer. As an outcome of these studies, it is also possible that a novel mechanism identified by this research may lead to the development of potential therapeutic targets to aid in preventing and/or treating obesity-associated colon cancer risk.