BLR&D Research Career Scientist Award Application

BLR

• 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
• 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' 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

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退伍军人管理局患者的主要健康问题 人口。有大量证据表明，肥胖会增加患各种癌症的风险。这个 弗吉尼亚州每年报告约40,000例新癌症病例，其中约2.7-3%是肝癌。肥胖与 代谢紊乱，如非酒精性脂肪性肝病(NAFLD)及其更严重的非酒精性脂肪肝 酒精性脂肪变性(NASH)，这些都是肝硬变和肝癌的危险因素。所以慢性肝病 疾病，无论是由病毒感染、饮酒、肥胖或其任何组合引起的，都是主要的风险。 导致肝硬变并最终导致肝癌的因素。退伍军人患肥胖症相关肝脏的风险很高 因此，了解该病的病因和发病机制是很重要的。 同样，肥胖人群中乳腺癌的发病率也在增加，流行病学证据表明 肥胖与乳腺癌之间的联系在绝经后的女性中尤为强烈。每八个女人中就有一个 将在他们的有生之年被诊断出患有乳腺癌。随着越来越多的女性参军 服务，妇女的健康问题成为退伍军人管理局更关注的问题。战场上暴露于毒物和 营养不良可能会引发代谢综合征，而代谢综合征与心脏病、糖尿病的风险更高 和癌症。研究以了解环境和营养事件如何影响正常 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 限时喂食高脂肪饮食。由于肥胖、胰岛素抵抗和乳腺癌之间的联系 绝经后妇女的风险，以及类似的时间限制的饮食干预可能 预防人类乳腺癌，重要的是要了解如何纠正胰岛素抵抗 降低小鼠乳腺癌生长的风险，并研究可能推动 肥胖中的肿瘤生长。 我们已经发表了肝细胞中一种特定的RNA剪接因子SRSF3的缺失导致慢性 肝损伤、糖脂代谢紊乱、炎症、纤维化，最终导致肝癌。 因此，剪接因子的缺失并不会导致肿瘤，而是会导致癌症的易感性，类似的 一种肿瘤抑制基因。自那以后，我们发现SRSF3的缺失在两种疾病的早期肝病中都被发现。 人类和小鼠，除了在肝癌中丢失外，SRSF3的丢失可能是引发 会引发进行性肝病。我们的研究将解决有关根本问题的关键问题 蛋白质动态平衡与肝脏癌变的生物过程及生化、细胞 以及对肝脏中缺乏特定剪接因子的小鼠进行生理学研究的分子生物学实验。 我们将研究阻止SRSF3在小鼠体内的降解是否足以阻止 早期的肝病到炎症、纤维化和肝硬变，我们将确定这种方法是否 预防肝癌或可用于逆转小鼠的肝癌。 最后，肥胖与组织炎症有关，我们已经证明，改变cAMP水平在 树突状细胞改变了它们指示T细胞发育成Th2或Th17谱系的能力。这一点很重要 作为Th2偏向的代谢后果可防止高脂饮食导致的肥胖和胰岛素抵抗。我们 进一步发现，诱导偏向Th17的炎症会加速小鼠肺癌的发生，并导致IL-2的丢失。 17A可防止肿瘤生长。我们的研究旨在了解炎症和疾病之间的联系 代谢，以及这些代谢如何改变肺癌的生长。这对VA患者来说是一个重要的研究领域 由于吸烟在退伍军人中很常见。