Metabolic Syndrome as Pancreatic Cancer Etiology

代谢综合征作为胰腺癌的病因

• 批准号: 7469288
• 负责人: JIN-RONG ZHOU
• 金额: $ 19.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469288
• 关键词: Address; Applications Grants; Cancer Etiology; Cardiovascular Diseases; Central obesity; Cessation of life; Development; Diabetes Mellitus; Diet; Fatty acid glycerol esters; Future; Glucose Intolerance; Goals; Growth Factor; Hypertension; Incidence; Intra-abdominal; Investigation; KRAS2 gene; Malignant neoplasm of pancreas; Metabolic; Metabolic syndrome; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Pancreatic Intraepithelial Neoplasia; Personal Satisfaction; Pilot Projects; Prevalence; Prevention; Public Health; Rate; Research Priority; Risk; Risk Factors; Serum; Tea; Testing; Transgenic Organisms; Treatment Protocols; Triglycerides; United States; Visceral; adipokines; cancer prevention; cancer risk; cancer type; design; improved; mortality; mouse model; prevent; sugar; tumor progression

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.

描述（由申请人提供）：该试点提案旨在解决PA- 06-303中强调的重要研究优先事项之一，旨在提供实验证据以确定代谢综合征（MS）是否是胰腺癌的可能病因。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，具有相似的发病率和死亡率。因此，降低胰腺癌风险和死亡率的唯一有效方案是通过早期预防。胰腺癌的有效预防需要针对明确的病因因素。然而，胰腺癌的病因尚未得到很好的理解。MS最初被描述为加速心血管疾病和2型糖尿病发作的一组风险因素，其特征在于内脏或腹内肥胖、葡萄糖耐受不良、高血压、低血清HDL-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，有限的实验证据可用于支持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是否是一个病因。我们的长期目标是测试MS是胰腺癌病因风险因素的假设，并且可以通过针对MS部分实现胰腺癌的有效预防。该试点开发提案旨在：（1）确定MS诱导是否刺激胰腺癌发展，（2）确定茶是否含有通过减轻MS部分地预防胰腺癌发展的活性成分。高单糖（HF/HS）诱导MS对转基因小鼠模型中胰腺癌发展的影响。通过使用转基因胰腺癌小鼠模型KRAS（G12 D），我们将确定HF/HS饮食诱导MS是否会刺激胰腺上皮内瘤形成（PanIN），以及哪些脂肪因子和生长因子将被调节。我们预期MS将刺激与某些脂肪因子和生长因子的调节相关的PanIN的形成和进展，特别是高级别PanIN。具体目标2是评估饮食茶组分对用正常或HF/HS饮食处理的小鼠中PanIN形成和进展的抑制作用。预计拟议的初步研究将提供实验证据，以支持或反对MS是否是胰腺癌发展的病因因素。研究结果还将为未来的R 01资助申请提供关键的实验证据，以进一步研究通过预防MS的发展和/或逆转代谢异常来预防胰腺癌的有效饮食/营养方案。公共卫生关系：该项目的目标是确定代谢综合征是否是胰腺癌进展的病因，并确定茶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。