Adipose-Specific Phosphatidic Acid Phosphatase Activity of Lipin 1 Regulates Systemic Insulin Sensitivity

脂质 1 的脂肪特异性磷脂酸磷酸酶活性调节全身胰岛素敏感性

基本信息

批准号：
10301629
负责人：
Andrew Lutkewitte
金额：
$ 13.11万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301629
关键词：
Acetylation Adipocytes Adipose tissue Animals Award Blood Blood Vessels Body Weight decreased Cardiometabolic Disease Cell Culture Techniques Data Development Development Plans Diglycerides Disease Enzyme Inhibition Fatty acid glycerol esters Funding Gene Expression Geriatrics Glucose Clamp Goals Half-Life Health Human Inflammatory Response Insulin Insulin Resistance Isotopes Knockout Mice Knowledge Laboratories Learning Link Lipids Lipolysis Lipoproteins Liver Lysine Mediating Mediator of activation protein Mentors Metabolic Metabolic stress Metabolism Modeling Modification Molecular Mus Muscle Mutagenesis Non-Insulin-Dependent Diabetes Mellitus Nutritional Science Obese Mice Obesity Pathology Phosphatidate Phosphatase Phosphatidic Acid Physiology Plasma Positioning Attribute Post-Translational Protein Processing Protein Inhibition Proteins Reporting Research Research Personnel Research Support Research Training Risk Role Scientist Secure Signal Transduction Skeletal Muscle Techniques Testing Thinness Time Tissues Tracer Training Triglycerides Universities Washington Work abdominal fat adipocyte differentiation cardiometabolism career development comorbidity enzyme activity improved in vivo insulin sensitivity insulin signaling lipid biosynthesis lipid metabolism lipidomics lipine liver injury lysophosphatidic acid medical schools metabolic phenotype metabolomics mouse model new therapeutic target non-alcoholic fatty liver disease novel obese patients overexpression particle peer coaching preservation prevent research and development skills uptake

项目摘要

ABSTRACT In this K01 Mentored Scientist Development Award application, Dr. Andrew J. Lutkewitte outlines a detailed strategy to further enhance his research training using sophisticated metabolic and lipidomic analysis. He will utilize these approaches to discover novel mediators of systemic insulin resistance driven by insufficient adipose tissue lipogenic capacity in obesity. Dr. Lutkewitte is currently a postdoctoral research fellow at Washington University School of Medicine’s Division of Geriatrics and Nutritional Sciences. He has a strong background in whole-body physiology and metabolism that he will draw upon to investigate adipose function during metabolic stress. A primary goal of Dr. Lutkewitte is to become and independent investigator in lipid metabolism and obesity-induced insulin resistance. He has carefully developed a research strategy with an integrated career development and mentoring plan to ensue realization of this goal. Each of the chosen mentors are leading experts in their respective fields which are directly related to this proposal. The primary mentor Dr. Brian Finck will assist with the metabolic characterization and analysis of both animal and cell culture models. From Dr. Nada Abumrad, he will learn stromal vascular fraction isolations, gain understanding about mechanisms of adipocyte differentiation and lipogenesis, and fundamentals of lipid uptake/export. Dr. Gary Patti will train Dr. Lutkewitte in both targeted and untargeted metabolomics as well as metabolic flux analysis using isotopic tracers in vivo. Besides research training, Dr. Finck and a “Near Peer” mentoring team will provide Dr. Lutkewitte with the essential skills to initiate and maintain a successful, independent laboratory. The ability of adipose tissue to regulate lipid stores (mainly, triglycerides) is vital for preserving metabolic health. In fact, an imbalance between the appropriate release (lipolysis) or synthesis (lipogenesis) of lipids in adipose tissue increases the risk of pathologies such as non-alcoholic fatty liver disease, systemic insulin resistance and ultimately type 2 diabetes. Yet, the fundamental mechanisms of how adipose tissue regulates systemic insulin sensitivity remain unclear. Recent evidence suggests that phosphatidic acid, the substrate for lipin 1, a phosphatidic acid phosphatase, is present at high levels in the blood and has deleterious effects in insulin sensitive tissues such as skeletal muscle and liver. The goals of this work are to: [1] determine how the posttranslational modification, acetylation, effects lipin 1 activity and cellular localization, [2] discover the specific acetylated lysine residues regulating lipin 1, [3] define how adipose tissue lipin 1 regulates whole-body metabolism and insulin sensitivity, and [4] to identify how phosphatidic acid and similar lipids mediate these effects. The end goal of this research progression is to develop Dr. Lutkewitte into a productive, independent investigator. Together the training in research and career development plan outlined here will provide him with the knowledge and expertise to secure an independent academic position and R01-type funding.

抽象的在这份 K01 导师科学家发展奖申请中，Andrew J. Lutkewitte 博士概述了详细的他将利用复杂的代谢和脂质组学分析进一步加强他的研究培训。这些方法发现由脂肪不足驱动的全身胰岛素抵抗的新介质 Lutkewitte 博士目前是华盛顿大学的博士后研究员。他在大学医学院老年病学和营养科学系拥有深厚的背景。他将利用全身生理学和新陈代谢来研究代谢过程中的脂肪功能 Lutkewitte 博士的首要目标是成为脂质代谢和压力方面的独立研究者。他精心制定了一项与肥胖引起的胰岛素抵抗相关的研究策略。发展和指导计划，以确保实现这一目标。每位选定的导师都是领导者。与本提案直接相关的各自领域的专家。将协助 Nada 博士对动物和细胞培养模型进行代谢表征和分析。 Abumrad，他将学习基质血管部分分离，了解脂肪细胞的机制 Gary Patti 博士将为 Lutkewitte 博士提供分化和脂肪生成以及脂质摄取/输出基础知识的培训。靶向和非靶向代谢组学以及体内使用同位素示踪剂的代谢流分析。除了研究培训之外，Finck 博士和“Near Peer”指导团队将为 Lutkewitte 博士提供启动和维持成功、独立实验室的基本技能脂肪组织的能力。调节脂质储存（主要是甘油三酯）对于保持代谢健康至关重要。事实上，两者之间的不平衡。脂肪组织中脂质的适当释放（脂肪分解）或合成（脂肪生成）会增加以下风险：诸如非酒精性脂肪肝、全身性胰岛素抵抗以及最终的 2 型糖尿病等病症。然而，脂肪组织如何调节全身胰岛素敏感性的基本机制仍不清楚。最近的证据表明，磷脂酸（脂质 1（一种磷脂酸磷酸酶）的底物）是血液中含量很高，对胰岛素敏感组织（如骨骼肌）有有害影响这项工作的目标是：[1] 确定翻译后修饰、乙酰化如何影响。脂质 1 活性和细胞定位，[2] 发现调节脂质 1 的特定乙酰化赖氨酸残基，[3] 定义脂肪组织脂质 1 如何调节全身代谢和胰岛素敏感性，并 [4] 确定如何磷脂酸和类似的脂质介导这些作用，本研究进展的最终目标是开发。 Lutkewitte 博士通过研究和职业培训成为一名富有成效的独立调查员。这里概述的发展计划将为他提供知识和专业知识，以确保独立学术地位和R01型资助。