BLR&D Research Career Scientist Award Application

BLR

基本信息

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
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/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&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

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&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

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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人口。有大量证据表明肥胖症承认各种形式癌症的风险增加。 VA报告每年约有40,000例新的癌症病例，约2.7-3％是肝癌。肥胖与代谢灾害，例如非酒精性脂肪肝疾病（NAFLD）及其更严重的非酒精疾病酒精脂肪变性（NASH），这些都是肝硬化和肝癌的危险因素。如此慢性肝疾病，无论是因病毒感染，饮酒，肥胖还是任何组合引起的疾病，都是主要风险肝硬化和最终肝癌的因素。退伍军人人口有与肥胖相关的肝脏的高风险疾病及其肝癌，因此重要的是要了解该疾病的病因和发病机理。同样，肥胖种群中乳腺癌的发生率也增加了，并且流行病学证据表明在绝经后妇女中，肥胖胸癌连接尤为强。八分之一的女人将在其一生中被诊断出患有乳腺癌。随着妇女人数越来越多服务，妇女的健康问题成为VA的更大关注点。战场暴露于有毒物质和不良的营养可能会触发与较高心脏病风险有关的代谢综合征和癌症。了解环境和营养事件如何影响正常的调节新陈代谢将对代谢失调如何增加各种疾病的风险进行更大的启示。我们发现，降低感染和胰岛素抵抗会减少小鼠的乳腺癌生长。这可以通过提供高水平的omega3脂肪酸或通过涉及的营养干预来完成高脂饮食的时间限制。由于肥胖，胰岛素抵抗与乳腺癌之间的联系绝经后妇女的风险，以及类似时间限制的饮食干预的潜力预防人类的乳腺癌，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，并研究可能驱动的身体变化肥胖症的肿瘤生长。我们已经发表了肝细胞中特定RNA剪接因子SRSF3的丢失会导致慢性肝损伤，葡萄糖和脂质代谢的干扰，感染，纤维化以及最终的肝癌。因此，剪接因子的丧失不会引起肿瘤，而是会引起癌症的前置态，类似到肿瘤抑制基因。此后，我们已经表明，在两者的早期肝病中都发现了SRSF3的损失人类和小鼠除了在肝癌中丧生外，因此SRSF3的损失可能是降水事件触发性肝脏疾病。我们的研究将解决有关基本的关键问题肝脏中蛋白质稳态和癌变的生物学过程，并将整合生化，细胞在缺乏肝脏中缺乏特定剪接因子的小鼠的物理研究中进行的分子生物学实验。我们将调查防止小鼠中SRSF3降解是否足以防止早期肝病炎症，纤维化和肝硬化，我们将确定这种方法是否防止肝癌或可用于逆转小鼠的肝癌。最后，肥胖与组织注射有关，我们已经表明，在树突状细胞改变了他们指导T细胞发展为Th2或Th17谱系的能力。这很重要代谢后果作为Th2偏置可防止高脂饮食诱导的肥胖和胰岛素抵抗。我们此外，发现诱导Th17偏置注射会加速小鼠的肺癌，并丧失IL- 17A防止肿瘤生长。我们的研究旨在了解炎症与代谢以及它们如何改变肺癌。这是VA患者的重要研究领域在退伍军人中，人口作为吸烟是普遍的。