Mechanisms for the regulation of novel lipids in vivo

体内新型脂质的调节机制

• 批准号: 10378638
• 负责人: Anna Santoro
• 金额: $ 15.07万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378638
• 关键词: Academia; Address; Adipocytes; Adipose tissue; Advisory Committees; Anabolism; Anti-Inflammatory Agents; Antidiabetic Drugs; Binding Proteins; Bioinformatics; Biological Assay; Biopsy; CRISPR/Cas technology; Carbohydrates; Computer Models; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Down-Regulation; Economic Burden; Endocrine; Environment; Enzymes; Esters; Etiology; Experimental Designs; Fasting; Funding; Future; GLUT 4 protein; Genes; Genetic; Genetic Models; Genetic Variation; Genomic Segment; Glucose Transporter; Goals; Grant; Hepatic; High Fat Diet; Human; Hydrolysis; Hydroxy Acids; Individual; Infusion procedures; Insulin; Insulin Resistance; Isotopes; Knockout Mice; Label; Lead; Life; Lipids; Mammalian Cell; Maps; Measures; Mediating; Mediation; Mentored Research Scientist Development Award; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Molecular; Molecular Biology; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Palmitic Acids; Pathway interactions; Periodicity; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Preparation; Process; Protocols documentation; Quantitative Trait Loci; Regulation; Research; Research Personnel; Response Elements; Role; Scientist; Serum; Site; Stearic Acids; Technology; Testing; Therapeutic; Tissues; Training; Triglycerides; United States National Institutes of Health; Variant; blood glucose regulation; career; career development; diabetic; enzyme biosynthesis; feeding; glucose tolerance; improved; in vivo; innovation; insight; insulin sensitivity; insulin sensitizing drugs; interest; knockout gene; lipid I; lipid biosynthesis; lipid metabolism; lipidomics; meetings; metabolomics; mouse model; multiple omics; novel; novel strategies; novel therapeutics; overexpression; post-doctoral training; prevent; programs; skills; social; trait; transcriptome sequencing; translational study

Project Summary/Abstract: Research: Insulin resistance is a major cause for type 2 Diabetes (T2D) and is implicated in many life- threatening complications of T2D. A better understanding of the molecular mechanisms for insulin resistance is essential to develop potent and safe insulin sensitizers, which could reduce the social and economic burden of metabolic diseases. Our lab discovered a novel class of anti-inflammatory and anti-diabetic lipids, Palmitic Acid Hydroxy Stearic Acids (PAHSAs). PAHSA levels strongly correlate with insulin sensitivity in humans and are down-regulated in adipose tissue (AT) from insulin resistant subjects. PAHSAs are potent hepatic and systemic insulin sensitizers in obese T2D mice. This project will identify the mechanisms for the regulation of PAHSAs in altered metabolic states in vivo and the enzymes mediating their biosynthesis and degradation, providing novel strategies to prevent or treat T2D. Specific Aim1: To determine the mechanisms that regulate PAHSA levels in vivo. Specific Aim2: To identify candidate enzymes for PAHSA biosynthesis and degradation in our unique genetic mouse models of altered glucose homeostasis. Specific Aim3: To identify natural genetic drivers of PAHSA metabolism using the established profiling of the natural genetic variation among 8 mouse strains to mimick human variation. These studies will uncover novel pathways at the crossroad between AT lipogenesis and insulin sensitivity that can be manipulated to prevent or treat T2D. Candidate’s career development plan and career goals: I am highly committed to elucidate the mechanisms for insulin resistance and T2D with the ultimate goal of expanding the therapeutic armamentarium for T2D. During my postdoctoral training in Dr. Barbara’s Kahn lab, I became interested in the connections between AT lipogenesis and systemic insulin sensitivity. During the K01 award, I will acquire the necessary skills to study lipid metabolism in vivo combining innovative and powerful multiomic approaches and molecular biology. The studies in this K01 proposal will be conducted under the mentorship of Drs. Kahn and Saghatelian with the guidance of an outstanding scientific advisory committee (Drs. Alan Attie, Joshua Rabinowitz, and Evan Rosen), who are highly committed to my development into an independent scientist. Periodic meetings with these experts will center on experimental design, discussion of results, future directions, and preparation of R01 and R03 grants. My long-term career goal is to become an NIH-funded independent scientist. The training received during this K01 award is necessary for my successful transition to independent investigator in the Academia. Environment: The BIDMC Endocrine Division is the ideal site for training of young scientists towards a path of independence because it offers unparalleled opportunities for interactions with leaders in the fields of diabetes and metabolism. Graduates from this Division have made transformative discoveries that open new trajectories for diabetes and metabolism research.

项目摘要/摘要： 研究：胰岛素抵抗是2型糖尿病（T2D）的主要原因，并且与许多生命有关 威胁T2D并发症。更好地了解胰岛素抵抗的分子机制是 开发潜在和安全的胰岛素传感器至关重要，这可以减少 代谢疾病。我们的实验室发现了一类新型的抗炎和抗糖尿病脂质，棕榈酸 羟耐硬脂酸（PAHSA）。 PAHSA水平与人类的胰岛素敏感性密切相关，并且是 来自胰岛素耐药受试者的脂肪组织（AT）下调。 PAHSA是潜在的肝和全身性的 肥胖T2D小鼠中的胰岛素传感器。该项目将确定对PAHSA的调节的机制 变化的代谢状态在体内和介导其生物合成和降解的酶提供新颖 预防或治疗T2D的策略。特定目标1：确定调节PAHSA水平的机制 体内。特定目标2：确定我们独特的PAHSA生物合成和降解的候选酶 葡萄糖稳态改变的遗传小鼠模型。特定目标3：确定自然遗传驱动因素 PAHSA代谢使用了8种小鼠菌株之间自然遗传变异的既定分析 模仿人类变异。这些研究将在脂肪生成之间发现十字路口的新途径 以及可以操纵以防止或治疗T2D的胰岛素敏感性。 候选人的职业发展计划和职业目标：我高度致力于阐明机制 对于胰岛素耐药性和T2D，其最终目标是扩大T2D治疗性武器库。期间 我在芭芭拉（Barbara）博士的卡恩（Kahn）实验室中的博士后培训，我对AT之间的联系感兴趣 脂肪生成和全身胰岛素敏感性。在K01奖中，我将获得学习的必要技能 体内脂质代谢结合了创新和强大的多构方法和分子生物学。这 该K01提案中的研究将根据DR的指导力量进行。 Kahn和Saghatelian与 杰出科学咨询委员会的指导（艾伦·阿蒂（Alan Attie），约书亚·拉比诺维茨（Joshua Rabinowitz）和埃文·罗森（Evan Rosen））， 谁致力于我成为独立科学家的发展。与这些专家的定期会议 将以实验设计，对结果的讨论，未来方向的讨论以及R01和R03的准备 赠款。我的长期职业目标是成为NIH资助的独立科学家。在 这项K01奖是我成功过渡到学术界独立研究者所必需的。 环境：BIDMC内分泌部是训练年轻科学家迈向的理想场所 独立性，因为它为与糖尿病领域的领导者互动提供了无与伦比的机会 和新陈代谢。来自该部门的毕业生已经进行了变革性的发现，可以开放新的轨迹 用于糖尿病和代谢研究。