BLR&D Research Career Scientist Award Application

BLR

基本信息

批准号：
10454119
负责人：
NICHOLAS J WEBSTER
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454119
关键词：
Accounting Address Adipose tissue Aging Alcohol consumption Alcoholism American Cancer Society Apoptosis Area Award Biochemical Biological Biological Process Breast Cancer Risk Factor Cancer Center Support Grant Cell Culture Techniques Cells Chronic Chronic Disease Cirrhosis Colon Carcinoma Colorectal Cancer Communication Cyclic AMP DNMT3B gene Dendritic Cells Developed Countries Development Diabetes Mellitus Diagnosis Dietary Intervention Direct Costs Disease Endocrinology Epidemiology Etiology Event Exposure to FN1 gene Facilities and Administrative Costs Fatty Acids Fibrosis Functional disorder Funding Goals Grant Growth Health Health Care Costs Hepatitis B Virus Hepatitis C virus Hepatocarcinogenesis Hepatocyte Hepatology High Fat Diet Hormonal Human Hyperglycemia Hyperinsulinism Impairment Incidence Inflammation Insulin Resistance Interleukin-17 Interruption Journals Knock-out Life Style Light Link Liver Liver diseases MDM2 gene MXD1 gene Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Medicine Metabolic Metabolic syndrome Metabolism Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Obesity associated liver disease Omega-3 Fatty Acids Oncogenes Overnutrition Overweight Paper Pathogenesis Patients Persons Phenotype Physiological Physiology Population Postmenopause Predisposition Prevalence Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Publishing RNA Splicing Regulation Reporting Reproductive Medicine Reproductive Sciences Research Resource Sharing Risk Risk Factors Scientist Signal Transduction Smoking Stimulus Survival Rate System T-Lymphocyte TP53 gene TP73 gene Time Time-restricted feeding Tissues Toxicant exposure Training Tumor Suppressor Genes United States National Academy of Sciences United States National Institutes of Health Veterans Virus Diseases Woman Women&apos s Health aurora B kinase career chronic liver disease clinical investigation cost design diabetes control diet-induced obesity effective therapy experimental study glucose metabolism heart disease risk high risk hypothalamic pituitary axis indexing interest lipid metabolism liver function liver inflammation liver injury liver metabolism malignant breast neoplasm military service military veteran mortality neoplastic cell new therapeutic target non-alcoholic non-alcoholic fatty liver disease novel therapeutic intervention nutrition obese person obesity risk patient population prevent proteostasis response targeted treatment toxicant tumor tumor growth

项目摘要

The morbidity and mortality associated with obesity is a major health problem in the VA patient population. There is abundant evidence that obesity confers increased risk for various forms of cancer. The VA reports ~40,000 new cases of cancer per year and ~2.7-3% are liver cancer. Obesity is associated with metabolic disturbances such as non-alcoholic fatty liver disease (NAFLD) and its more severe form non- alcoholic steatosis (NASH) and these are risk factors for both cirrhosis and liver cancer. So chronic liver disease, whether induced by viral infection, alcohol use, obesity or any combination thereof, is the major risk factor for cirrhosis and ultimately liver cancer. The Veteran population is at high risk for obesity-associated liver disease and hence liver cancer so it is important to understand the etiology and pathogenesis of the disease. Similarly the incidence of breast cancer is increased in obese populations, and the epidemiologic evidence for the obesity-breast cancer connection is particularly strong in post-menopausal women. One in eight women will be diagnosed with breast cancer during their lifetime. As increasing numbers of women enter military service, women’s health issues become a greater concern for the VA. Battlefield exposures to toxicants and bad nutrition may trigger the metabolic syndrome that is associated with higher risk of heart disease, diabetes and cancer. Studies to understand how environmental and nutritional events impact the regulation of normal metabolism will shed greater light on how metabolic dysregulation increases the risk of various diseases. We have found that reducing inflammation and insulin resistance reduces breast cancer growth in mice. This can be done by providing high levels of omega3 fatty acids or through a nutritional intervention involving time-restricted feeding of a high-fat diet. Due to the link between obesity, insulin resistance and breast cancer risk in post-menopausal women, and the potential that a similar time-restricted, dietary intervention could protect against breast cancer in humans, it is important to understand how correcting insulin resistance reduces the risk of breast cancer growth in mice and investigate the physiological changes that may drive tumor growth in obesity. We have published that loss of a particular RNA splicing factor SRSF3 in hepatocytes causes chronic liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer. So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both humans and mice, in addition to being lost in liver cancer, so loss of SRSF3 may be the precipitating event that triggers progressive liver disease. Our studies will address key questions concerning the fundamental biological process of protein homeostasis and carcinogenesis in the liver and will integrate biochemical, cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will investigate whether preventing degradation of SRSF3 in mice is sufficient to prevent the progression of early liver disease to inflammation, fibrosis and cirrhosis, and we will determine whether this approach prevents liver cancer or can be used to reverse liver cancer in mice. Lastly, obesity is associated with tissue inflammation and we have shown that altering cAMP levels in dendritic cells changes their ability to instruct T cells to develop into Th2 or Th17 lineages. This has important metabolic consequences as a Th2 bias prevents high-fat diet induced obesity and insulin resistance. We furthermore found that induction of a Th17 biased inflammation accelerates lung cancer in mice, and loss of IL- 17A prevents tumor growth. Our studies are designed to understand the link between inflammation and metabolism, and how these alter lung cancer growth. This is an important area of research for the VA patient population as smoking is common among veterans.

与肥胖相关的发病率和死亡率是 VA 患者的主要健康问题有大量证据表明肥胖会增加患各种癌症的风险。 VA 报告每年约 40,000 例新发癌症病例，其中约 2.7-3% 是肝癌与肥胖有关。代谢紊乱，例如非酒精性脂肪肝（NAFLD）及其更严重的非酒精性脂肪肝酒精性脂肪变性（NASH），这些都是肝硬化和肝癌的危险因素。疾病，无论是由病毒感染、饮酒、肥胖或其任意组合引起的，都是主要风险退伍军人人群患肥胖相关肝癌的风险很高。因此，了解该疾病的病因和发病机制非常重要。同样，肥胖人群中乳腺癌的发病率也会增加，并且流行病学证据表明在八分之一的绝经后女性中，肥胖与乳腺癌的关系尤其密切。随着越来越多的女性参军，她们将在一生中被诊断出患有乳腺癌。服役期间，女性的健康问题成为退伍军人管理局在战场上接触有毒物质和环境的一个更大的问题。营养不良可能引发代谢综合征，从而增加患心脏病、糖尿病的风险研究了解环境和营养事件如何影响正常的调节。新陈代谢将更好地揭示代谢失调如何增加各种疾病的风险。我们发现减少炎症和胰岛素抵抗可以减少小鼠乳腺癌的生长。这可以通过提供高水平的 omega3 脂肪酸或通过营养干预来实现由于肥胖、胰岛素抵抗和乳腺癌之间的联系，限制时间喂养高脂肪饮食。绝经后妇女的风险，以及类似的限时饮食干预的潜力预防人类乳腺癌，了解如何纠正胰岛素抵抗非常重要降低小鼠乳腺癌生长的风险并研究可能驱动乳腺癌生长的生理变化肥胖时肿瘤生长。我们发表了肝细胞中特定 RNA 剪接因子 SRSF3 的丢失会导致慢性肝脏损伤、葡萄糖和脂质代谢紊乱、炎症、纤维化，最终导致肝癌。因此，剪接因子的丢失不会导致肿瘤，而是会产生癌症的倾向，类似此后我们发现，在两种疾病的早期肝病中都发现了 SRSF3 的缺失。人类和小鼠中，除了在肝癌中丢失外，SRSF3 的丢失可能是导致引发进行性肝病。我们的研究将解决有关基本问题的关键问题。肝脏中蛋白质稳态和癌变的生物过程，并将整合生化、细胞以及在肝脏中缺乏特定剪接因子的小鼠中进行的分子生物学实验和生理研究。我们将研究阻止小鼠中 SRSF3 的降解是否足以阻止疾病的进展早期肝病发展为炎症、纤维化和肝硬化，我们将确定这种方法是否有效预防肝癌或可用于逆转小鼠肝癌。最后，肥胖与组织炎症有关，我们已经证明改变 cAMP 水平树突状细胞改变了指导 T 细胞发育成 Th2 或 Th17 谱系的能力，这一点很重要。 Th2 偏好的代谢后果可防止高脂肪饮食引起的肥胖和胰岛素抵抗。此外还发现，诱导 Th17 偏向性炎症会加速小鼠肺癌的发生，并且 IL- 17A 可以预防肿瘤生长。新陈代谢，以及它们如何改变肺癌的生长，这是 VA 患者的一个重要研究领域。因为吸烟在退伍军人中很常见。