BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10219156
• 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/10219156
• 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; 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VA患者的主要健康问题