Role of SIRT3 in fetal programming and kidney dysfunction

简介（由申请人提供）：科罗拉多大学丹佛分校的应用物理学家和蛋白质组学专家，Karen Jonscher博士的首要目标是运用她独特的技能，以及从不同领域协同信息的天生能力，进行创造性的假设发展和独立追求创新和富有成果的应用生物医学研究事业。她的长期目标是应用定量分析和生物信息学方法来了解线粒体功能障碍和氧化应激在肥胖相关疾病中的作用。她的短期研究重点和拟建研究的主题是研究暴露于母亲过度营养计划中肾脏线粒体功能障碍未来变化的分子机制，从而导致早发性肾病。这个K25奖项将为Jonscher博士提供必要的支持，以实现以下目标：1)获得所需的教育背景，将她的想法牢牢地固定在她正在研究的系统的基础生物学和营养生物化学上；2)获得对拟议工作和她未来独立研究重要的分子和细胞生物学方法的接触；3)学习在她的研究中实施尖端的代谢组学技术；4)成为最先进的显微镜技术专家，用于研究蛋白质信号和脂质代谢；5)为指导成功和学术领导建立新的技能；6)制定一个研究计划，使她能够作为一名独立的生物医学研究者成功竞争。为了实现这些目标，Jonscher博士充分利用了科罗拉多大学丹佛市中心分校和Anschutz医学院的优秀教育资源，以及科罗拉多临床和转化科学研究所（NIH UL1 TR000154）、营养和肥胖研究中心（P30 DK048520）、内分泌学、糖尿病和代谢学部、先进的光学显微镜核心设施和代谢核心实验室来设计她的职业发展和培训计划。重要的是，她组建了一个世界知名的指导团队，其中包括主要导师杰德·弗里德曼博士，他的实验室研究了母体肥胖和妊娠糖尿病（GDM）的代谢和遗传原因和后果，以及肥胖的早期发育起源；共同导师Moshe Levi博士，肾脏病理生理学和高级显微镜专家，研究肥胖、糖尿病和年龄相关肾脏和血管疾病发病机制中磷酸盐和脂质代谢的调节；Jane Reusch博士是一位临床内分泌学家，专注于了解糖尿病、高血糖和氧化应激如何调节血管疾病中cAMP反应元件结合蛋白的活性；指导老师Robert Rucker博士，一位营养生物化学家专家，对阐明吡咯喹啉醌（PQQ）在细胞和线粒体中的作用机制感兴趣；Manisha Patel博士的专长是研究神经系统疾病中的氧化应激和线粒体功能障碍；Sean Colgan博士是上皮细胞生物学专家，专注于缺氧在疾病中的机制作用。每个团队成员将协助研究计划的特定方面，提供协议和方法开发，故障排除和数据解释方面的帮助。这些高级院士将帮助指导Jonscher博士的职业道路，为领导实验室和成功指导学生提供建议，并使她能够在更广泛的科学界建立新的合作和网络，从而促进她向独立过渡。成人代谢性疾病流行病在幼儿中的出现是一个巨大的公共卫生问题，也是Jonscher博士研究目标的重点。可能在这种病因中起关键作用的全球因素包括母亲的饮食和代谢；线粒体功能障碍和氧化应激是潜在的重要分子驱动因素。然而，与母体营养过剩相关的早期细胞起源和组织特异性功能障碍，特别是肾脏，仍有待确定，疾病生物标志物尚未很好地建立。Jonscher博士令人信服和新颖的初步数据显示，暴露于母亲肥胖的幼年后代肾脏中的脂质积累、胶原沉积和蛋白质超乙酰化发生了改变，这表明乙酰化在调节对高脂质负荷的代谢反应中发挥了作用。她建议使用发育编程的高脂肪饮食小鼠模型来表征早发性肾脏疾病（Aim 1）的定量组织学、生化和细胞标志物，并将它们与功能重要的蛋白质组学和代谢组学变化（Aim 2）联系起来。在使用抗氧化剂吡咯喹啉醌（PQQ）干预以挽救表型（Aim 3）后，将重新评估Aims 1和2的终点。这些将是第一批研究：1)量化由母亲肥胖引起的肾脏脂质代谢的改变；2)确定母亲脂质暴露后肾脏代谢中蛋白质超乙酰化的功能后果；3)确定SIRT3在调节线粒体对母亲过度营养反应中的潜在作用；4)在怀孕和哺乳期给予有效的抗氧化剂，以挽救发育过程中的“脂毒性”。这些研究的结果将为Jonscher博士未来的独立研究提供新的蛋白质和代谢物靶点，并为代谢性疾病可能传播的机制提供新的见解。

DESCRIPTION (provided by applicant): An Applied Physicist and proteomics expert at the University of Colorado Denver, Dr. Karen Jonscher's overarching goal is to apply her unique skill set, and an innate ability to synergize information from varied fields, toward creative hypothesis development and the independent pursuit of an innovative and productive applied biomedical research career. Her long-term objective is to apply quantitative analytical and bioinformatic approaches to understand the role of mitochondrial dysfunction and oxidative stress in obesity- related disease. Her short-term focus, and the subject of the proposed research, is to investigate molecular mechanisms whereby exposure to maternal over-nutrition programs future changes in kidney mitochondrial dysfunction, resulting in early-onset nephropathy. This K25 award will provide Dr. Jonscher with the support necessary to accomplish the following goals: 1) attain the educational background required to firmly anchor her ideas in the underlying biology and nutritional biochemistry of the systems she is investigating, 2) obtain exposure to molecular and cellular biology approaches that are important for the proposed work and her future independent research, 3) learn to implement cutting-edge metabolomic techniques in her research, 4) become expert at state-of-the-art advanced microscopy techniques used to investigate protein signaling and lipid metabolism, 5) build new skills for mentoring success and academic leadership and 6) develop a research program that will allow her to successfully compete as an independent biomedical investigator. To achieve these goals, Dr. Jonscher has capitalized on the outstanding educational resources available at the University of Colorado Denver Downtown and Anschutz Medical Campuses, as well as those provided by the Colorado Clinical and Translational Science Institute (NIH UL1 TR000154), the Nutrition and Obesity Research Center (P30 DK048520), the Division of Endocrinology, Diabetes and Metabolism, the Advanced Light Microscopy Core Facility and the Metabolic Core Lab in the design of her career development and training plan. Importantly, she has assembled a world-renowned mentoring team comprised of primary mentor Dr. Jed Friedman, whose lab investigates metabolic and genetic causes and consequences of maternal obesity and gestational diabetes mellitus (GDM) on the early developmental origins of obesity; co- mentor Dr. Moshe Levi, an expert in renal pathophysiology and advanced microscopy, studying regulation of phosphate and lipid metabolism in the pathogenesis of obesity, diabetes mellitus and age-related renal and vascular disease; advisor Dr. Jane Reusch, a clinical endocrinologist focused on understanding how diabetes, hyperglycemia and oxidative stress modulate activity of the cAMP Response Element Binding Protein in vascular disease; advisor Dr. Robert Rucker, an expert nutritional biochemist interested in elucidating the mechanism of action of pyrroloquinoline quinone (PQQ) in cells and mitochondria; advisor Dr. Manisha Patel, whose expertise lies in the study of oxidative stress and mitochondrial dysfunction in neurological disease, and advisor Dr. Sean Colgan, an expert epithelial cell biologist focused on the mechanistic role of hypoxia in disease. Each team member will assist with specific aspects of the research plan, offering help with protocols and method development, troubleshooting, and data interpretation. These senior-level academicians will help guide Dr. Jonscher's career path, provide advice on leading a laboratory and successfully mentoring students, and enable her to establish new collaborations and networks within the broader scientific community that will facilitate her transition to independence. The emergence of adult metabolic disease epidemics in young children is an enormous public health concern and is the focus of Dr. Jonscher's research goals. Global factors that may play a key role in this etiology include maternal diet and metabolism; mitochondrial dysfunction and oxidative stress are potentially important molecular drivers. However, early cellular origins and tissue-specific dysfunction related to maternal over-nutrition, particularly in the kidney, remain to be identified and disease biomarkers are not well established. Dr. Jonscher's compelling and novel preliminary data show altered lipid accumulation, collagen deposition and protein hyperacetylation in kidneys from juvenile offspring exposed to maternal obesity, suggesting a role for acetylation in regulating the metabolic response to high lipid loads. She proposes to characterize quantitative histological, biochemical and cellular markers of early-onset kidney disease (Aim 1) and correlate them with functionally important proteomic and metabolomic changes (Aim 2) using a high-fat diet mouse model of developmental programming. Endpoints of Aims 1 and 2 will be reassessed following intervention using the anti-oxidant pyrroloquinoline quinone (PQQ) to rescue the phenotype (Aim 3). These will be the first studies to 1) quantify alterations in renal lipid metabolism inducd by maternal obesity, 2) determine functional consequences of protein hyperacetylation in kidney metabolism following maternal lipid exposure, 3) identify a potential role for SIRT3 in regulating mitochondrial response to maternal over-nutrition, and 4) administer a potent anti-oxidant during pregnancy and lactation to rescue developmentally programmed "lipotoxicity." Results from these studies will provide novel protein and metabolite targets for Dr. Jonscher's future independent investigations and fresh insights into mechanisms by which metabolic disease may be propagated.