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.

该申请是为了支持劳伦·阿什利·考特（Lauren Ashley Cowart）博士，博士为VA研究职业科学家。考特博士 自2005年以来一直是VA资助的，并一直担任2个NIH R01奖项（目前由2025年资助）， 除其他壁外支撑外。 Cowart博士在拉尔夫·H·约翰逊（Ralph H. Johnson）开始了她的独立职业 VAMC及其学术会员，南卡罗来纳州医科大学（MUSC）。当她在那里发展时 NIH和VA的强大研究计划都支持生物活性鞘脂的贡献 致肥胖相关疾病。这些研究包括有关不同脂肪酸如何（例如，不饱和， ）饱和等）细胞中修饰的鞘脂代谢，以及鞘脂的异常产生如何导致 炎症，适应不良的自噬，氧化应激和其他有害程序。这些研究是 在各种器官和组织中进行，包括骨骼肌，心肌，肝脏和脂肪组织。 拉尔夫·H·约翰逊·瓦姆（Ralph H. Johnson VAMC）的研究环境非常丰富，在那里她出版了40多个 手稿包括8个与著名的VA合作者。从2005年至2017年，Cowart博士从一项研究中进步 终身副教授的田径助理教授。 2017年，考特博士搬到了猎人福尔摩斯 McGuire VAMC的学术会员是弗吉尼亚联邦大学。她立即​​与 VA心脏病专家Edward Lesnnefsky博士，她最近的VA优异奖授予共同投资者，并与 她有积极的研究项目和出版物的准备。最近她开发了项目 与其他VAMC的调查员，包括圣路易斯的Abhinav Diwan博士（John Cochran Vamc/Wash。U.）， 这导致了一些赠款和手稿的准备，而SAN的Sushil Mahata博士 迭戈（VA San Diego Healthcare System/UCSD），她有两个手稿，并且有 正在积极申请NIH和VA资金（通过协作功绩计划）。而规模 Hunter Holmes McGuire的基础科学研究企业比Ralph H. Johnson狭窄 继续寻找并在弗吉尼亚州当地和国家弗吉尼亚州研究社区内进行新的合作。 Cowart博士的研究涉及代谢疾病的星座：2型糖尿病，肥胖症， 代谢综合征和非酒精性脂肪肝病。在这种情况下，她的工作解决了分子 鞘脂调节脂肪组织功能，非酒精性脂肪肝病（NAFLD）的机制， 和心肌功能障碍。主要发表的发现包括饱和与不饱和脂肪酸 差异调节酶，包括产生鞘脂介质的鞘氨醇激酶1（SPHK1） 鞘氨醇1-磷酸盐（S1P）和神经酰胺，鞘氨醇1-磷酸盐介导NAFLD。这些 调查结果使她发展了SPHK1的细胞特异性击球效果。令人惊讶的是，脂肪细胞特异性的SPHK1鼠标 表现出基本的糖尿病样表型，表明SPHK1在脂肪细胞中具有有益的稳态作用。 此外，在肝脏中，肝细胞中SPHK1的耗竭部分减弱了NAFLD的炎症，但 雌性小鼠，而不是雄性，出现了恶化的纤维化表型，这导致发现 雌激素诱导的S1P从肝细胞中释放，对肝星状细胞具有抗纤维化作用。尽管 她的小组在肥胖饮食上使用小鼠进行其他研究，发现抑制鞘脂生物合成 阻止小鼠发展心脏肥大和糖尿病心肌病的特征。更远 细胞中的机理研究表明，神经酰胺合酶5介导的不良适应自噬， 相比之下，神经酰胺合酶2介导的ROS产生和线粒体。这些高度引用的手稿 反映了剖析心脏病中鞘脂合成复杂性的第一部作品 病理基础的不同途径。这些既定的研究为当前工作奠定了基础 进一步解决与肥胖相关病理学，酒精性肝病和脂质的生物活性鞘脂 生物标志物发现。当她继续发展研究时，该奖项将提供稳定和连续性。