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，结肠癌病例将会增加；因此，关于肥胖如何增加结肠癌风险的研究是非常及时和重要的，并将影响未来的几代人。脂肪组织分泌荷尔蒙和细胞因子(脂肪因子)，这些激素和细胞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、白介素6(IL-6)和脂联素是三种脂肪因子，它们可能在肥胖相关的癌症进展中发挥直接作用。虽然这些荷尔蒙/细胞因子在稳态浓度下对正常的细胞功能至关重要，但当水平从正常水平改变(如肥胖)时，它们可能是病理性的。炎症性结肠癌是炎症性肠病中一种众所周知的临床现象，炎性刺激可促进启动的肿瘤细胞的存活和增殖。我们假设脂肪因子的失衡是肿瘤前细胞的关键促炎信号。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，存在着一个关键的缺口。因此，这项研究的长期目标是了解肥胖相关的系统性脂肪因子升高是如何增加结肠癌风险的。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。这项应用通过临床前模型研究了瘦素在癌前病变而不是正常结肠上皮细胞中激活的差异细胞信号和蛋白水解酶机制。结肠癌的肿瘤性转化具有很好的特征性。我们将利用与转化范式一致的正常和癌前病变结肠上皮细胞来解决这一应用的两个特定目标的中心假设：1)确定与瘦素诱导(和脂联素阻断)IL-6信号增殖有关的差异转录因子；2)鉴定导致瘦素诱导癌前病变和正常结肠上皮细胞间可溶性白介素6受体差异脱落的蛋白酶。预计一旦确定肥胖诱发结肠癌的这一生物学机制，就有可能针对这一机制。这项应用中的研究与公共健康相关，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于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的机制也可能导致开发潜在的治疗靶点，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.