NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS

鞘脂在维持血管稳态方面的新作用

• 批准号: 10063902
• 负责人: Julie K Freed
• 金额: $ 14.98万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063902
• 关键词: Adipocytes; Adult; Advisory Committees; Affect; Affinity; American; Anesthesiology; Anti-Inflammatory Agents; Antiinflammatory Effect; Atherosclerosis; Award; Biological; Biological Availability; Biometry; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Ceramidase; Ceramides; Chronic; Clinical Trials Design; Coronary; Coronary Arteriosclerosis; Disease; Endothelium; Environment; Enzymes; Equilibrium; Event; Exposure to; Family; Functional disorder; Generations; Goals; Grant; Health; Heart; Heart Atrium; Homeostasis; Human; Hydrogen Peroxide; Image; Individual; Inflammation; Inflammatory; Knowledge; Laboratories; Leadership; Liquid Chromatography; Mass Spectrum Analysis; Measurement; Measures; Mediator of activation protein; Medical Imaging; Mentors; Metabolism; Microcirculation; Modeling; Nitric Oxide; Outcome; Oxidative Stress; Pathway interactions; Patients; Perfusion; Pharmacology; Phase; Phosphorylation; Physiological; Plasma; Prevention; Production; Research; Research Personnel; Risk Factors; Role; Sampling; Societies; Sphingolipids; Sphingomyelinase; Sphingosine; Students; Techniques; Technology; Time; Tissue Sample; Tissue imaging; Tissues; Training; Translating; Vasodilation; Woman; Work; Writing; adiponectin; arteriole; ceramide 1-phosphate; clinical Diagnosis; cytokine; experience; in vivo; instrumentation; lipid mediator; meetings; men; new technology; novel; overexpression; programs; receptor; response; sabbatical; skills; sphingosine 1-phosphate; symposium; tandem mass spectrometry; thrombotic

Project Summary The studies proposed for this K08 application will use unique approaches to examine the effects of sphingolipid metabolism on the mediator of flow-induced vasodilation (FID) within the human vasculature. Recently it has been shown that ceramide, a bioactive sphingolipid known to be elevated in the plasma of patients with cardiovascular disease, is an independent predictor of major adverse cardiovascular events. A potential way ceramide could adversely affect outcomes is by its recently discovered effect on the mediator of FID. Arterioles exposed to ceramide dilate in response to flow by generating H2O2, a pro-inflammatory and pro- atherosclerotic mediator as opposed to nitric oxide (NO), the anti-inflammatory, anti-atherosclerotic mediator utilized by healthy adults in response to increased flow. On the contrary, sphingosine-1-phosphate (S1P), also within the sphingolipid family and a metabolite of ceramide, promotes NO-dependent FID. How sphingolipids affect vasoactive mediators formed during flow and impact vascular homeostasis remains largely unknown. The aims of this proposal examine how the balance of sphingolipids, also known as the `sphingolipid rheostat,' influences the generation of a specific FID mediator which will have a profound impact on the formation or prevention of inflammation and atherosclerosis. Overall this application represents the necessary first step to define the mechanistic role of sphingolipid metabolism during FID in the human microcirculation. The training plan during the award phase will expand my scientific skill set in four ways. First, I will expand my training and experience using an established human vascular reactivity model to investigate how sphingolipid metabolism and the S1P:ceramide ratio determine the mediator of FID. Second, during a sabbatical in the laboratory of Dr. Ruikang Wang, I will receive training in tissue imaging, specifically in vivo microvascular imaging, with the goal of adapting a new technology (CytoCam) to translate our findings to the whole human. I will also receive training from Dr. Andrew Morris, in how to measure sphingolipids from small human samples using liquid chromatography tandem mass spectrometry (LC MS/MS). This instrumentation is available at MCW but has not been adapted for sphingolipid measurements. Bringing this technology to MCW will greatly strengthen my research program and support others needing to quantify lipid mediators in small tissue samples. Third, I will complete formal coursework in biostatistics, grant writing, advanced mass spectrometry techniques, clinical trial design, and medical imaging. These courses were specifically chosen by me and my mentoring team to supplement my formal training, and will provide vital knowledge as I continue to develop into an independent investigator. The fourth component of this training plan involves taking on leadership roles, such as being a mentor to students, managing an affinity group consisted of clinicians and researchers, organizing symposia at national meetings, and serving on scientific advisory committees for the American Society of Anesthesiology. The first three of these components are already in progress.

项目摘要 为K 08申请提出的研究将使用独特的方法来检查 鞘脂代谢对人体血管系统内流动诱导的血管舒张（FID）介质的影响。 最近，研究表明，神经酰胺是一种生物活性鞘脂，已知在糖尿病患者血浆中升高， 心血管疾病患者，是主要不良心血管事件的独立预测因子。一 神经酰胺可能对结果产生不利影响的潜在方式是其最近发现的对 FID的暴露于神经酰胺的小动脉通过产生H2 O2（一种促炎和促炎因子）对流量作出反应而扩张。 与抗炎、抗动脉粥样硬化介质一氧化氮（NO）相反， 被健康的成年人用来应对增加的流量。相反，鞘氨醇-1-磷酸（S1 P），也 属于鞘脂家族，是神经酰胺的代谢物，促进NO依赖性FID。鞘脂如何 影响流动过程中形成的血管活性介质和影响血管内稳态仍然是未知的。 该提案的目的是研究鞘脂的平衡，也称为“鞘脂变阻器”， 影响特定FID介体的产生，这将对地层产生深远影响，或 预防炎症和动脉粥样硬化。总的来说，这一应用程序是必要的第一步， 定义在人微循环中FID期间鞘脂代谢的机制作用。 获奖阶段的培训计划将从四个方面扩展我的科学技能。首先我会 使用已建立的人体血管反应性模型扩展我的培训和经验，以研究如何 鞘脂代谢和S1 P：神经酰胺比率决定FID的介体。第二，在A 在王瑞康博士的实验室休假期间，我将接受组织成像方面的培训，特别是在体内 微血管成像，目标是采用新技术（CytoCam）将我们的发现转化为 整个人类。我还将接受安德鲁·莫里斯博士的培训，学习如何从小到大测量鞘脂。 使用液相色谱串联质谱法（LC MS/MS）测定人样品。该仪器是 可在MCW获得，但尚未适用于鞘脂测量。将这项技术带到MCW 将大大加强我的研究计划，并支持其他需要量化脂质介质在小 组织样本第三，我将完成生物统计学，资助写作，高级质量 光谱技术、临床试验设计和医学成像。这些课程是由 我和我的指导团队补充我的正式培训，并将提供重要的知识，因为我继续 成为一名独立的调查员。该培训计划的第四个组成部分涉及承担 领导角色，例如作为学生的导师，管理由临床医生组成的亲和团体， 研究人员，在国家会议上组织专题讨论会，并担任科学咨询委员会的成员， 美国麻醉学会。其中前三个组成部分已经在进行中。