Role of SIRT3 in fetal programming and kidney dysfunction

SIRT3 在胎儿编程和肾功能障碍中的作用

• 批准号: 8998019
• 负责人: KAREN R JONSCHER
• 金额: $ 13.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998019
• 关键词: Acetylation; Adolescent; Adult; Affect; Albumins; Animal Model; Antioxidants; Appearance; Award; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Biology; Biomedical Research; Blood Pressure; Cardiovascular Diseases; Career Choice; Cells; Child; Childhood; Clinical; Clinical Sciences; Collaborations; Collagen; Colorado; Communities; Comorbidity; Core Facility; Cyclic AMP-Responsive DNA-Binding Protein; Data; Data Analyses; Deacetylase; Deposition; Development; Diabesity; Diabetes Mellitus; Diet; Disease; Educational Background; Endocrinologist; Endocrinology; Enzymes; Epidemic; Epithelial Cells; Etiology; Exposure to; Fatty Liver; Female of child bearing age; Fetal Kidney; Functional disorder; Future; Genetic; Gestational Diabetes; Glomerular Filtration Rate; Glucose; Goals; Health; Hepatic; High Fat Diet; Hyperglycemia; Hypertension; Hypoxia; Incidence; Infant; Injury; Institutes; Insulin; Insulin Resistance; Intervention; Intervention Studies; Investigation; Kidney; Kidney Diseases; Laboratories; Lactation; Lead; Leadership; Learning; Lipids; Liver; Liver diseases; Measures; Mediating; Medical; Mentors; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Molecular and Cellular Biology; Mothers; Mus; Nutritional; Nutritional Biochemistry; Obese Mice; Obesity; Obesity associated disease; Output; Overweight; Oxidative Stress; PQQ Cofactor; Pathogenesis; Perinatal Exposure; Phenotype; Play; Post-Translational Protein Processing; Pregnancy; Prevalence; Proteins; Proteomics; Protocols documentation; Public Health; Publications; Publishing; Regulation; Renal Vascular Disorder; Renal function; Research; Research Personnel; Resources; Role; Serum; Signaling Protein; Stress; System; Techniques; Testing; Time; Tissues; Training; Translational Research; United States National Institutes of Health; Universities; Vascular Diseases; Weaning; Western World; Work; age related; animal data; base; career; career development; design; early onset; experience; fetal programming; good diet; human data; immunoaffinity chromatography; improved; in utero; indexing; innovation; inorganic phosphate; insight; interest; kidney metabolism; light microscopy; lipid metabolism; mature animal; member; metabolomics; method development; mitochondrial dysfunction; mouse model; nervous system disorder; nonhuman primate; novel; nutrition; offspring; podocyte; prevent; programs; protein metabolite; ranpirnase; response; skills; student mentoring; success; trend; urinary

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.

描述（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博士的总体目标是运用她的独特技能，并具有先天的能力，可以使各种领域，创造性的假设发展和独立的创新和生产性应用生物研究职业的知识来协调信息。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。她的短期关注点以及拟议的研究的主题是研究分子机制，从而暴露于母体过度营养计划的未来肾脏线粒体功能障碍的未来变化，从而导致早期发作的肾病。 该K25奖将为实现以下目标提供必要的支持：1）获得确定她正在研究的系统的基本生物学和营养生物化学所需的教育背景，2）在用于研究蛋白质信号传导和脂质代谢的最先进的高级显微镜技术中，5）为指导成功和学术领导而建立新的技能； 6）制定了一项研究计划，该计划将使她能够成功地成为独立的生物医学研究员。 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在她的职业发展和培训计划的设计中，设施和代谢核心实验室。重要的是，她组建了一个由主要导师杰德·弗里德曼（Jed Friedman）博士组成的世界知名团队，他的实验室调查了孕产妇肥胖和妊娠糖尿病（GDM）对肥胖的早期发育起源的代谢和遗传原因以及后果；肾脏病理生理学和晚期显微镜专家Moshe Levi博士研究了肥胖症，糖尿病以及与年龄有关的肾脏和血管疾病的调节。顾问Jane Reusch博士，一名临床内分泌学家Jane Reusch博士，致力于了解糖尿病，高血糖和氧化应激如何调节cAMP反应元件结合蛋白在血管疾病中的活性；顾问Robert Rucker博士是一名专家营养生物化学家，兴趣阐明细胞和线粒体中吡咯烷酚喹酮（PQQ）的作用机理；顾问Manisha Patel博士的专业知识在于神经疾病中氧化应激和线粒体功能障碍的研究，以及专家上皮细胞生物学家Sean Colgan顾问Sean Colgan博士，专注于低氧在疾病中的机械作用。每个团队成员将协助研究计划的具体方面，为协议和方法开发，故障排除和数据解释提供帮助。这些高级院士将帮助指导琼斯博士的职业道路，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，以促进她向独立过渡。 成人代谢疾病流行病在幼儿中的出现是一个巨大的公共卫生问题，是琼斯博士的研究目标的重点。在这种病因中可能起关键作用的全球因素包括孕产妇饮食和代谢；线粒体功能障碍和氧化应激可能是重要的分子驱动因素。然而，早期的细胞起源和组织特异性功能障碍与孕产妇过度营养有关，尤其是在肾脏中，仍有待鉴定，并且疾病生物标志物尚未得到很好的确定。 Jonscher博士的引人入胜且新颖的初步数据显示，暴露于母体肥胖的幼年后代的肾脏积累，胶原蛋白沉积和蛋白质高乙基化改变了，这表明乙酰化在调节高脂质负荷的代谢反应中起作用。她提议表征早期发作肾脏疾病的定量组织学，生化和细胞标记（AIM 1），并使用发育计划的高脂饮食鼠标模型将它们与功能上重要的蛋白质组学和代谢组变化（AIM 2）相关。干预后，将重新评估目标1和2的终点，使用抗氧化吡咯喹啉醌（PQQ）营救表型（AIM 3）。这些将是最早的研究1）量化孕产妇肥胖诱导肾脏脂质代谢的变化，2）确定蛋白质脂质暴露后蛋白质高乙基化在肾脏代谢中的功能后果，3）确定SIRT 3在调节孕产妇过度静脉和4）对孕产物静脉的反应中的潜在作用，并且是4）potifie to and to antimiption and 4）。开发编程的“脂肪毒性”。这些研究的结果将为琼斯博士的未来独立研究以及对可以传播代谢疾病的机制提供新的蛋白质和代谢物靶标。