Molecular basis for dietary chemoprevention

 描述（由申请人提供）：如果医疗保健界希望阻止即将到来的癌症风暴，我们需要尽快更加认真地预防癌症。不幸的是，只有不到1.5%的生物医学研究资金用于早期发现和预防慢性病。在所有人类恶性肿瘤中，35%与饮食直接相关，另外14-20%与肥胖相关。与这些数据一致，当人类坚持健康的饮食原则时，癌症风险可以降低36%。建立癌症饮食化学预防方法的因果关系，这些方法不存在长期给药药物固有的安全性问题，将对癌症预防和患者生存产生重大的转化影响。因此，我们的总体目标是更好地了解将肠上皮细胞反应与饮食来源的天然植物产品以及结肠癌风险的内源性（肠道微生物）修饰剂联系起来的分子（核和质膜靶向）机制。我们在饮食化学预防领域的丰富经验为我们提供了这方面的独特机制视角。我们提出了两个新的研究主题。项目1将评估芳烃受体（AhR）配体作为结肠干细胞稳态和恶性转化决定因素的联合激动剂和拮抗剂作用。迄今为止，我们的研究表明，AhR配体对干细胞有深刻的短期影响，并可能有利于恶性转化。项目2旨在确定是否通过改变细胞膜液体有序纳米级组件，并因此改变蛋白质空间定位和信号传导，选择两亲性膳食剂将减少致癌K-Ras信号传导，从而减少肿瘤发生。这种策略与我们实验室和其他实验室最近的报道一致，这些报道选择两亲性药物，通过直接调节质膜的生物物理性质，改变致癌K-Ras纳米簇并抑制信号转导。

 DESCRIPTION (provided by applicant): If the healthcare community hopes to head off the impending cancer storm, we need to get more serious about cancer prevention soon. Unfortunately, less than 1.5% of total biomedical research funding is targeted to early detection and prevention of chronic disease. With respect to all human malignancies, 35% are linked directly to diet and an additional 14-20% to obesity. Consistent with these data, cancer risk can be lowered by 36% when humans adhere to healthy dietary principles. Establishing a causal role for cancer dietary chemoprevention approaches that are free of safety problems intrinsic to drugs administered over long periods of time would have a major translational impact in cancer prevention and patient survivorship. Therefore, our overall goal is to better understand the molecular (nuclear and plasma membrane targeted) mechanisms linking intestinal epithelial cell responses to diet-derived natural botanical products, and endogenous (gut microbial) modifiers of colon cancer risk. Our extensive experience in the dietary chemoprevention field has afforded us with a unique mechanistic perspective in this regard. We propose to pursue two novel research themes. Project 1 will assess the combined agonist and antagonistic role of Arylhydrocarbon Receptor (AhR) ligands as determinants in colon stem cell homeostasis and malignant transformation. Our studies to date indicate that AhR ligands have profound short-term effects on stemness, and may be beneficial in terms of malignant transformation. Project 2 is designed to determine whether by altering cell membrane liquid ordered nanoscale assemblies, and therefore protein spatial localization and signaling, that select amphiphilic dietary agents will reduce oncogenic K-Ras signaling leading to reduced tumorigenesis. This strategy is consistent with recent reports from our lab and others that select amphiphilic agents, through direct modulation of the biophysical properties of the plasma membrane, alter oncogenic K- Ras nanoclustering and suppress signal transduction.