BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10703523
• 负责人: Lauren Ashley Cowart
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703523
• 关键词: Address; Adipocytes; Adipose tissue; Afghanistan; Alcoholic Liver Diseases; Anabolism; Applications Grants; Atherosclerosis; Attenuated; Autophagocytosis; Award; Back; Basic Science; Bibliography; Biological Markers; Blood; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Ceramides; Collaborations; Communities; Complement Factor H; Development; Diabetes Mellitus; Diet; Disease; Doctor of Philosophy; Environment; Enzymes; Estrogens; Extramural Activities; Faculty; Fatty Acids; Female; Foundations; Funding; Grant; Health; Healthcare Systems; Heart Diseases; Heart Hypertrophy; Heart failure; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Inflammation; International; Investigation; Investments; Iraq; Joints; K-Series Research Career Programs; Knock-out; Knockout Mice; Laboratories; Laws; Link; Lipids; Liver; Liver diseases; Manuscripts; Mediating; Mediator; Medical; Mental Depression; Mental disorders; Mentors; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Mus; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Myristates; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated disease; Oleic Acids; Organ; Overweight; Oxidative Stress; Palmitates; Palmitic Acids; Pathology; Pathway interactions; Phenotype; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Preparation; Production; Publications; Publishing; Regulation; Research; Research Personnel; Research Project Grants; Risk Factors; Role; SPHK1 enzyme; Scientist; Seminal; Signal Transduction; Skeletal Muscle; South Carolina; Sphingolipids; TBI Patients; Thermogenesis; Tissues; Training; Traumatic Brain Injury; United States National Institutes of Health; Universities; Unsaturated Fatty Acids; Veterans; Virginia; War; Work; alcohol use disorder; base; biomarker discovery; career; diabetic cardiomyopathy; dihydroceramide desaturase; experience; fatty liver disease; forging; high risk; inhibitor; interest; lipid metabolism; member; mid-career faculty; mouse model; non-alcoholic; non-alcoholic fatty liver disease; novel; obesogenic; prevent; problem drinker; professor; programs; risk prediction; sphingosine 1-phosphate; synergism

This application is to support Dr. Lauren Ashley Cowart, PhD as a VA Research Career Scientist. Dr. Cowart has been VA funded since 2005 and has served as PI on 2 NIH R01 awards (currently funded through 2025), among other intra- and extramural support. Dr. Cowart began her independent career at the Ralph H. Johnson VAMC and its academic affiliate, the Medical University of South Carolina (MUSC). While there she developed a robust research program with both NIH and VA support addressing the contribution of bioactive sphingolipids to obesity-related disease. These studies included seminal work on how different fatty acids (e.g unsaturated, saturated, etc.) modified sphingolipid metabolism in cells, and how aberrant production of sphingolipids led to inflammation, maladaptive autophagy, oxidative stress, and other deleterious programs. These studies were conducted in a variety of organs and tissues including skeletal muscle, cardiac muscle, liver, and adipose tissue. The research environment at Ralph H. Johnson VAMC was very rich, and while there she published over 40 manuscripts including 8 with prominent VA collaborators. From 2005-2017 Dr. Cowart advanced from a research track Assistant Professor to a tenured Associate Professor. In 2017, Dr. Cowart moved to the Hunter Holmes McGuire VAMC whose academic affiliate is Virginia Commonwealth University. She immediately connected with Dr. Edward Lesnefsky, a VA cardiologist who serves co-investigator on her recent VA Merit award, and with whom she has active research projects and publications in preparation. Recently she has developed projects with investigators at other VAMCs including Dr. Abhinav Diwan in St. Louis (John Cochran VAMC/Wash. U.), which has resulted in several grant applications and manuscripts in preparation, and Dr. Sushil Mahata in San Diego (VA San Diego Healthcare System/UCSD), with whom she has two manuscripts in development and has been actively applying for both NIH and VA funding (through the collaborative Merit program). While the scale of the basic science research enterprise at Hunter Holmes McGuire is narrower than at Ralph H. Johnson, she continues to seek out and forge new collaborations within the local VA and national VA research community. Dr. Cowart’s research addresses the constellation of metabolic diseases: type 2 diabetes, obesity, metabolic syndrome, and non-alcoholic fatty liver disease. In this context her work addresses molecular mechanisms by which sphingolipids regulate adipose tissue function, non-alcoholic fatty liver disease (NAFLD), and myocardial dysfunction. Major published findings include that saturated vs. unsaturated fatty acids differentially regulate enzymes including sphingosine kinase 1 (SphK1) that produce the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide, and that sphingosine-1-phosphate mediates NAFLD. These findings led her to develop cell-specific knock outs of SphK1. Surprisingly, the adipocyte-specific SphK1 mouse demonstrated a basal diabetes-like phenotype, indicating a beneficial, homeostatic role for SphK1 in adipocytes. Furthermore, in liver, while depletion of SphK1 in hepatocytes partially attenuated inflammation in NAFLD, female mice, and not males, developed an exacerbated fibrotic phenotype, which led to the discovery that estrogen-induced release of S1P from hepatocytes had an anti-fibrotic effect on hepatic stellate cells. While using mice on obesogenic diets for other studies, her group discovered that inhibition of sphingolipid biosynthesis prevented mice from developing cardiac hypertrophy and features of diabetic cardiomyopathy. Further mechanistic studies in cells showed that specifically, Ceramide Synthase 5 mediated maladaptive autophagy, and in contrast Ceramide Synthase 2 mediated ROS production and mitophagy. These highly cited manuscripts reflect the first work that has dissected the complexities of sphingolipid synthesis in heart disease to reveal distinct pathways that underlie pathology. These established studies have laid a foundation for current work further addressing bioactive sphingolipids in obesity-related pathology, alcoholic liver disease, and lipid biomarker discovery. This award will provide stability and continuity as she continues to develop her research.

此应用程序是为了支持劳伦阿什利Cowart博士，博士作为一个VA研究职业科学家。科沃特医生 自2005年以来一直获得VA资助，并担任2项NIH R 01奖的PI（目前资助至2025年）， 以及其他校内和校外的支持。Cowart博士在Ralph H.约翰逊 VAMC及其学术附属机构，南卡罗来纳州医科大学（MUSC）。在那里，她开发了 在NIH和VA的支持下，开展了一项强有力的研究计划，以解决生物活性鞘脂的贡献 与肥胖有关的疾病。这些研究包括关于不同脂肪酸（如不饱和脂肪酸， 饱和等）细胞中鞘脂代谢的改变，以及鞘脂的异常产生如何导致 炎症、适应不良自噬、氧化应激和其他有害程序。这些研究 在包括骨骼肌、心肌、肝和脂肪组织的多种器官和组织中进行。 在拉尔夫H的研究环境。约翰逊VAMC非常富有，在那里她出版了40多本书。 手稿，包括8与著名的VA合作者。从2005年到2017年，Cowart博士从一项研究 从助理教授升为终身副教授2017年，Cowart博士搬到了Hunter Holmes McGuire VAMC，其学术附属机构是弗吉尼亚联邦大学。她立即与 博士Edward Lesnefsky是一位退伍军人事务部心脏病专家，她最近获得了退伍军人事务部优秀奖， 她正在准备积极的研究项目和出版物。最近她开发了一些项目， 与其他VAMC的研究人员，包括圣路易斯的Abhinav Diwan博士（John Cochran VAMC/Wash. U.）， 这导致了几个赠款申请和手稿的准备，和博士Sushil Mahata在圣 迭戈（弗吉尼亚州圣地亚哥医疗保健系统/加州大学圣地亚哥分校），与她有两个手稿的发展， 一直积极申请NIH和VA资金（通过合作优异计划）。虽然规模 Hunter Holmes McGuire的基础科学研究事业比Ralph H.约翰逊，她 继续寻求并在当地VA和国家VA研究界建立新的合作。 Cowart博士的研究涉及代谢疾病的星座：2型糖尿病，肥胖， 代谢综合征和非酒精性脂肪肝。在这方面，她的工作涉及分子 鞘脂调节脂肪组织功能的机制，非酒精性脂肪性肝病（NAFLD）， 和心肌功能障碍。已发表的主要研究结果包括饱和脂肪酸与不饱和脂肪酸 差异调节酶，包括产生鞘脂介质的鞘氨醇激酶1（SphK 1 鞘氨醇-1-磷酸（S1 P）和神经酰胺，且鞘氨醇-1-磷酸介导NAFLD。这些 这些发现使她开发出了SphK 1的细胞特异性敲除。令人惊讶的是，脂肪细胞特异性SphK 1小鼠 证明了基础糖尿病样表型，表明SphK 1在脂肪细胞中具有有益的稳态作用。 此外，在肝脏中，虽然肝细胞中SphK 1的缺失部分减轻了NAFLD中的炎症， 雌性小鼠，而不是雄性小鼠，发展出恶化的纤维化表型，这导致发现， 雌激素诱导肝细胞释放S1 P对肝星状细胞具有抗纤维化作用。而 她的研究小组在其他研究中使用了致肥饮食的小鼠， 防止小鼠出现心脏肥大和糖尿病性心肌病的特征。进一步 细胞中的机制研究表明，特别是神经酰胺合酶5介导的适应不良自噬， 而神经酰胺合成酶2介导ROS产生和线粒体自噬。这些被高度引用的手稿 反映了第一个工作，解剖了心脏病中鞘脂合成的复杂性， 不同的病理学路径这些既定的研究为当前的工作奠定了基础 进一步解决肥胖相关病理学、酒精性肝病和脂质中的生物活性鞘脂 生物标志物发现这个奖项将提供稳定性和连续性，因为她继续发展她的研究。