Mechanisms for the regulation of novel lipids in vivo

项目概要/摘要： 研究：胰岛素抵抗是2型糖尿病（T2 D）的主要原因，并与许多生活相关。 2型糖尿病的危险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，这可以减少社会和经济负担， 代谢性疾病我们的实验室发现了一种新型的抗炎和抗糖尿病的脂质，棕榈酸 羟基硬脂酸（PAHSAs）。PAHSA水平与人类的胰岛素敏感性密切相关， 在来自胰岛素抵抗受试者的脂肪组织（AT）中下调。PAHSAs是强效的肝脏和全身 肥胖T2 D小鼠中的胰岛素增敏剂。该项目将确定在以下方面管制多环芳烃的机制： 改变体内代谢状态和介导其生物合成和降解的酶，提供了新的 预防或治疗T2 D的策略。具体目标1：确定调节PAHSA水平的机制， vivo.具体目标2：在我们独特的细胞中鉴定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：确定自然遗传驱动因素， PAHSA代谢使用8个小鼠品系之间已建立的天然遗传变异谱， 模仿人类的变异这些研究将揭示AT脂肪生成之间的十字路口的新途径 和胰岛素敏感性，可以被操纵来预防或治疗T2 D。 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 用于胰岛素抵抗和T2 D，最终目标是扩展T2 D的治疗设备。期间 我在芭芭拉博士的卡恩实验室的博士后培训，我开始感兴趣的AT之间的联系， 脂肪生成和全身胰岛素敏感性。在K 01奖学金期间，我将获得必要的学习技能 脂质代谢在体内结合创新和强大的多组学方法和分子生物学。的 K 01提案中的研究将在Kahn博士和Saghatelian博士的指导下进行， 一个杰出的科学咨询委员会（艾伦·阿蒂博士，约书亚拉比诺维茨，埃文罗森）的指导， 他们都致力于让我成为一名独立的科学家与这些专家定期举行会议 将集中于实验设计、结果讨论、未来方向以及R 01和R 03的制备 赠款。我的长期职业目标是成为NIH资助的独立科学家。期间接受的培训 这个K 01奖是我成功过渡到学术界独立调查员的必要条件。 环境：BIDMC内分泌部是培养年轻科学家的理想场所， 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 和新陈代谢。该部门的毕业生取得了变革性的发现，开辟了新的轨迹 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.