Mechanisms for the regulation of novel lipids in vivo

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，与许多生活方式有关- T2D的严重并发症。更好地理解胰岛素抵抗的分子机制是 开发有效和安全的胰岛素增敏剂至关重要，这可以减少 代谢性疾病。我们实验室发现了一种新的抗炎抗糖尿病脂类--棕榈酸 羟基硬脂酸(PAHSA)。PAHSA水平与人类的胰岛素敏感性密切相关，并且 胰岛素抵抗受试者脂肪组织(AT)表达下调。PAHSA对肝脏和全身都很有效 肥胖T2D小鼠中的胰岛素增敏剂。该项目将确定#年多环芳烃的监管机制。 体内代谢状态的改变以及介导其生物合成和降解的酶，提供了新的 预防或治疗T2D的策略。特异性Aim1：确定体内PAHSA水平的调节机制 活着。特异的AIM2：确定PAHSA在我们独特的 葡萄糖动态平衡改变的小鼠遗传模型。特异目的3：确定自然遗传因素 利用已建立的8个品系小鼠之间自然遗传变异的图谱进行PAHSA代谢 模仿人类的变异。这些研究将在AT脂肪生成的十字路口发现新的途径 和胰岛素敏感性，可以被操纵来预防或治疗T2D。 应聘者的职业发展计划和职业目标：我高度致力于阐明这些机制 用于胰岛素抵抗和T2D，最终目标是扩大T2D的治疗设备。在.期间 我在芭芭拉博士的卡恩实验室接受博士后培训后，我开始对AT之间的联系感兴趣 脂肪生成和全身性胰岛素敏感性。在K01奖项期间，我将获得学习所需的技能 体内脂肪代谢结合创新和强大的多组学方法和分子生物学。这个 K01提案中的研究将在Kahn博士和Saghatelian博士的指导下进行，并与 杰出的科学顾问委员会(艾伦·阿蒂、约书亚·拉比诺维茨和埃文·罗森博士)的指导， 他们高度致力于我成为一名独立科学家的发展。与这些专家定期举行会议 将集中于R01和R03的实验设计、结果讨论、未来方向和准备 资助金。我的长期职业目标是成为一名由NIH资助的独立科学家。在此期间接受的培训 这一K01奖项对于我成功过渡到学术界的独立研究员来说是必要的。 环境：BIDMC内分泌部是培训年轻科学家走上 独立性，因为它为糖尿病领域的领导者提供了无与伦比的互动机会 和新陈代谢。这个部门的毕业生取得了革命性的发现，开启了新的轨迹 用于糖尿病和新陈代谢研究。

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.