Metabolic Syndrome as Pancreatic Cancer Etiology

描述(由申请人提供)：这项试验性提案旨在解决PA-06-303中强调的重要研究重点之一，旨在提供实验证据，以确定代谢综合征(MS)是否为胰腺癌的可能病因。胰腺癌是美国癌症死亡的第四大原因，也是最致命的癌症类型之一，发病率和死亡率相似。因此，降低胰腺癌风险和死亡率的唯一有效方案是早期预防。胰腺癌的有效预防需要针对明确的病因。然而，胰腺癌的病因学还不是很清楚。MS最初被描述为一组加速心血管疾病和2型糖尿病发病的危险因素，其特征是内脏或腹内肥胖、葡萄糖耐量减低、高血压、血清低密度脂蛋白-C和高血清甘油三酯。流行病学调查表明，肥胖和糖尿病与胰腺癌风险增加有关。然而，只有有限的实验证据可以支持MS是否是胰腺癌的病因因素。随着MS患病率的增加以及胰腺癌风险和死亡率的增加，迫切需要提供明确的实验证据来证明MS是否是病因。我们的长期目标是检验MS是胰腺癌病因学风险因素的假设，并且可以在一定程度上通过靶向MS来有效预防胰腺癌。此试验性开发方案旨在：(1)确定MS诱导是否刺激胰腺癌的发生；(2)确定TEA是否包含有效成分，部分通过减轻MS的症状来预防胰腺癌的发生；具体目标1是在转基因小鼠模型中确定高脂/高单糖(HF/HS)诱导的MS对胰腺癌发生的影响。通过使用转基因胰腺癌小鼠模型KRAS(G12D)，我们将确定HF/HS饮食诱导的MS是否会刺激胰腺上皮内瘤变(Panin)的形成，以及哪些脂肪因子和生长因子将受到调控。我们预计MS将刺激Panin的形成和进展，特别是高级别Panin，与某些脂肪因子和生长因子的调节有关。具体目的2是评估饮食茶成分对正常或HF/HS饮食处理的小鼠抑制Panin形成和进展的影响。预计拟议的先导性研究将提供实验证据，支持或反对多发性硬化症是否为胰腺癌发生的病因因素。这些结果还将为未来的R01拨款申请提供关键的实验证据，以进一步研究有效的饮食/营养方案，通过防止MS的发展和/或逆转代谢异常来预防胰腺癌。公共卫生相关性：拟议项目的目标是确定代谢综合征是否是胰腺癌进展的病因因素，以及确定TEA生物活性成分是否部分通过改善代谢谱和逆转代谢异常来抑制胰腺癌进展。

DESCRIPTION (provided by applicant): This pilot proposal, designed to address one of the important research priorities highlighted in the PA- 06-303, is to provide experimental evidence to determine if metabolic syndrome (MS) serves as a possible etiological factor for pancreatic cancer. Pancreatic cancer is the 4th leading cause of cancer death in the United States, and is one of the deadliest cancer types, with the similar incidence and mortality rates. Thus the only effective regimen to reduce pancreatic cancer risk and mortality is via early prevention. Effective prevention of pancreatic cancer requires target on defined etiological factors. However, the pancreatic cancer etiology has not been well understood. MS, which is initially described as a cluster of risk factors that accelerates the onset of cardiovascular disease and type 2 diabetes, is characterized by visceral or intra- abdominal obesity, glucose intolerance, hypertension, low serum HDL-C and high serum triglycerides. Epidemiological investigations have suggested that obesity and diabetes are associated with increased risk of pancreatic cancer. However, limited experimental evidence is available to support if MS is an etiological factor for pancreatic cancer. With increasing prevalence of MS and in parallel increasing pancreatic cancer risk and mortality, there is an urgent need to provide definitive experimental evidence to demonstrate if MS is an etiological factor. Our long-term goal is to test the hypotheses that MS is an etiological risk factor for pancreatic cancer, and effective prevention of pancreatic cancer can be achieved in part by targeting MS. This pilot developmental proposal is designed: (1) to determine if MS induction stimulates pancreatic cancer development, (2) to determine if tea contains active ingredients to prevent pancreatic cancer development in part by alleviating MS. Specific Aim 1 is to determine the effects of the high fat/high simple sugar (HF/HS)-induced MS on pancreatic cancer development in a transgenic mouse model. By using the transgenic pancreatic cancer mouse model, the KRAS (G12D), we will determine if induction of MS by the HF/HS diet will stimulate formation of pancreatic intraepithelial neoplasia (PanIN), and which adipokines and growth factors will be modulated. We expect that the MS will stimulate the formation and progression of PanIN, especially high grade PanIN, associated with modulation of certain adipokines and growth factors. Specific Aim 2 is to evaluate the effects of dietary tea components on inhibiting PanIN formation and progression in mice treated with normal or HF/HS diets. It is expected that the proposed pilot studies will provide experimental evidence to support or against if MS is an etiological factor for pancreatic cancer development. The results will also provide crucial experimental evidence for a future R01 grant application to further investigate effective dietary/nutritional regimens for pancreatic cancer prevention by preventing the development of MS and/or reversing metabolic abnormalities. PUBLIC HEALTH RELEVANCE: The goals of the proposed project are to determine if metabolic syndrome is an etiological factor for pancreatic cancer progression, and to determine if tea bioactive components inhibit pancreatic cancer progression in part by improving metabolic profiles and reversing metabolic abnormalities.