Mechanisms for the regulation of novel lipids in vivo

体内新型脂质的调节机制

• 批准号: 10186875
• 负责人: Anna Santoro
• 金额: $ 15.22万
• 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/10186875
• 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; 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，与许多生活密切相关。 更好地了解胰岛素抵抗的分子机制是 T2D 的威胁并发症。 开发有效且安全的胰岛素增敏剂至关重要，这可以减轻人们的社会和经济负担 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。 羟基硬脂酸 (PAHSA) 水平与人类胰岛素敏感性密切相关。 PAHSA 在胰岛素抵抗受试者的脂肪组织 (AT) 中下调，对肝脏和全身都有作用。 肥胖 T2D 小鼠中的胰岛素增敏剂 该项目将确定 PAHSA 的调节机制。 改变体内代谢状态以及介导其生物合成和降解的酶，提供新的 预防或治疗 T2D 的策略 具体目标 1：确定调节 PAHSA 水平的机制。 具体目标2：在我们独特的方法中鉴定 PAHSA 生物合成和降解的候选酶。 改变葡萄糖稳态的遗传小鼠模型 具体目标3：确定葡萄糖稳态的自然遗传驱动因素。 PAHSA 代谢利用 8 种小鼠品系之间已建立的自然遗传变异分析来 模仿人类变异。这些研究将揭示 AT 脂肪生成之间的新途径。 以及可以控制胰岛素敏感性来预防或治疗 T2D。 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 胰岛素抵抗和 T2D 的最终目标是扩大 T2D 的治疗手段。 在 Barbara 博士的 Kahn 实验室接受博士后培训后，我对 AT 之间的联系产生了兴趣 在获得 K01 奖励期间，我将获得学习必要的技能。 体内脂质代谢结合了创新且强大的多组学方法和分子生物学。 K01 提案中的研究将在 Kahn 和 Saghatelian 博士的指导下进行。 杰出科学顾问委员会（Alan Attie、Joshua Rabinowitz 和 Evan Rosen 博士）的指导， 他们高度致力于我成为一名独立科学家，定期与这些专家会面。 将集中于实验设计、结果讨论、未来方向以及 R01 和 R03 的准备 我的长期职业目标是成为一名 NIH 资助的独立科学家。 这个 K01 奖项对于我成功过渡到学术界的独立研究者来说是必要的。 环境：BIDMC 内分泌部门是培训年轻科学家走向未来之路的理想场所 独立性，因为它提供了与糖尿病领域领导者互动的无与伦比的机会 该部门的毕业生取得了开创性的发现，开辟了新的轨迹。 用于糖尿病和代谢研究。