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.

此申请旨在支持 Lauren Ashley Cowart 博士作为 VA 研究职业科学家。 自 2005 年以来一直获得 VA 资助，并担任 2 个 NIH R01 奖项的 PI（目前资助至 2025 年）， Cowart 博士在 Ralph H. Johnson 开始了她的独立职业生涯。 VAMC 及其学术附属机构南卡罗来纳医科大学 (MUSC) 是她在该大学发展起来的。 NIH 和 VA 支持的一项强有力的研究计划，旨在解决生物活性鞘脂的贡献 这些研究包括关于不同脂肪酸（例如不饱和脂肪酸）如何影响肥胖相关疾病的开创性工作。 饱和等）改变了细胞中的鞘脂代谢，以及鞘脂的异常产生如何导致 这些研究涉及炎症、适应不良的自噬、氧化应激和其他有害程序。 在多种器官和组织中进行，包括骨骼肌、心肌、肝脏和脂肪组织。 Ralph H. Johnson VAMC 的研究环境非常丰富，在那里她发表了 40 多篇论文 2005 年至 2017 年间，Cowart 博士从一项研究中取得进展，其中包括 8 篇与 VA 著名合作者合作的手稿。 2017 年，Cowart 博士从助理教授晋升为终身副教授。 McGuire VAMC 的学术附属机构是弗吉尼亚联邦大学，她立即与她建立了联系。 Edward Lesnefsky 博士是退伍军人事务部心脏病专家，最近担任退伍军人事务部优异奖的联合研究员，并与 她正在准备积极的研究项目和出版物。最近她开发了项目。 与其他 VAMC 的研究人员合作，包括圣路易斯的 Abhinav Diwan 博士（John Cochran VAMC/华盛顿大学）， 这导致了几项资助申请和正在准备的手稿，以及圣路易斯的 Sushil Mahata 博士 迭戈（弗吉尼亚州圣地亚哥医疗系统/加州大学圣地亚哥分校），她与他一起编写了两份手稿，并已 一直在积极申请 NIH 和 VA 的资助（通过合作优异计划）。 Hunter Holmes McGuire 的基础科学研究事业比 Ralph H. Johnson 的范围更窄，她 继续在当地 VA 和国家 VA 研究界寻求并建立新的合作。 Cowart 博士的研究涉及一系列代谢疾病：2 型糖尿病、肥胖、 在此背景下，她的工作涉及分子疾病。 鞘脂调节脂肪组织功能、非酒精性脂肪肝（NAFLD）的机制， 已发表的主要研究结果包括饱和脂肪酸与不饱和脂肪酸。 差异性调节酶，包括产生鞘脂介质的鞘氨醇激酶 1 (SphK1) 1-磷酸鞘氨醇 (S1P) 和神经酰胺，1-磷酸鞘氨醇介导 NAFLD。 令人惊讶的是，这些发现促使她开发出细胞特异性敲除 SphK1 的脂肪细胞特异性 SphK1 小鼠。 类似糖尿病的表型，表明 SphK1 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 SphK1 的消耗部分减轻了 NAFLD 中的炎症， 雌性小鼠（而非雄性小鼠）出现了加剧的纤维化表型，这导致了以下发现： 雌激素诱导的肝细胞释放 S1P 对肝星状细胞具有抗纤维化作用。 她的团队使用致肥胖饮食的小鼠进行其他研究，发现鞘脂生物合成的抑制 防止小鼠出现心脏肥大和糖尿病性心肌病的特征。 细胞机制研究表明，神经酰胺合酶 5 介导的适应不良自噬， 相比之下，神经酰胺合酶 2 介导 ROS 产生和线粒体自噬。这些被高度引用的手稿。 反映了第一个剖析心脏病中鞘脂合成复杂性的工作，以揭示 这些已建立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 该奖项将为她继续发展研究提供稳定性和连续性。