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: 8796181
• 负责人: KAREN R JONSCHER
• 金额: $ 13.12万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8796181
• 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; Deacetylase; Deposition; Development; Diabesity; Diabetes Mellitus; Diet; Disease; Educational Background; Endocrinologist; Endocrinology; Enzymes; Epidemic; Epithelial Cells; Etiology; Exposure to; Fatty Liver; Fatty acid glycerol esters; Female of child bearing age; Fetal Kidney; Functional disorder; Future; Genetic; Gestational Diabetes; Glomerular Filtration Rate; Glucose; Goals; Health; Hepatic; 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 function; Research; Research Personnel; Resources; Role; Serum; Signaling Protein; Stress; Students; 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; 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(申请人提供)：Karen Jonscher博士是科罗拉多丹佛大学的应用物理学家和蛋白质组学专家，她的首要目标是应用她独特的技能和天生的能力，从不同的领域协同信息，进行创造性的假说开发和独立追求创新和富有成效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。她的短期重点，也是拟议研究的主题，是研究母亲过度营养计划的分子机制，通过这些机制，母亲过度营养计划可能会改变肾脏线粒体功能障碍，导致早发性肾病。这项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，以坚定地将她的想法固定在她正在研究的系统的基本生物学和营养生物化学中；2)接触对拟议工作和她未来的独立研究非常重要的分子和细胞生物学方法；3)学习在她的研究中实施尖端新陈代谢技术；4)成为用于研究蛋白质信号和脂肪代谢的最先进的显微技术的专家。5)建立指导成功和学术领导的新技能，6)开发一个研究项目，使她能够作为一名独立的生物医学研究员成功竞争。为了实现这些目标，Jonscher博士利用科罗拉多大学丹佛市中心和安舒茨医学院现有的优秀教育资源，以及由科罗拉多临床和翻译科学研究所(NIH UL1 TR000154)、营养与肥胖研究中心(P30 DK048520)、内分泌学、糖尿病和新陈代谢学部、高级光学显微镜核心设备和代谢核心实验室提供的资源，设计了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导师团队，成员包括初级导师Jed Friedman博士，其实验室调查母亲肥胖和妊娠期糖尿病(GDM)对肥胖早期发育起源的代谢和遗传原因及后果；共同导师Mohe Levi博士，肾脏病理生理学和高级显微镜专家，研究肥胖症、糖尿病以及与年龄相关的肾脏和血管疾病发病机制中磷酸盐和脂肪代谢的调节；临床内分泌学家Jane Reusch博士，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；专家顾问Robert Rucker博士致力于阐明吡咯喹啉醌(PQQ)在细胞和线粒体中的作用机制；Manisha Patel博士的专业知识在于研究神经系统疾病中的氧化应激和线粒体功能障碍；Sean Colgan博士是一位专注于低氧在疾病中的机制作用的上皮细胞生物学家专家。每个团队成员将协助研究计划的特定方面，在协议和方法开发、故障排除和数据解释方面提供帮助。这些高级院士将帮助指导乔舍尔博士的职业道路，提供领导实验室和成功指导学生的建议，并使她能够在更广泛的科学界建立新的合作和网络，这将促进她向独立的过渡。成人代谢性疾病流行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。可能在这一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可能是重要的分子驱动因素。然而，与母亲过度营养有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，疾病生物标记物也没有得到很好的确定。Jonscher博士令人信服的、新颖的初步数据显示，暴露于母体肥胖的幼年后代肾脏中的脂肪堆积、胶原沉积和蛋白质超乙酰化发生了变化，这表明乙酰化在调节高脂负荷下的代谢反应中发挥了作用。她建议利用发育编程的高脂饮食小鼠模型，表征早期肾病的定量组织学、生化和细胞标记物(目标1)，并将它们与重要的蛋白质组和代谢组学变化(目标2)相关联。在使用抗氧化剂吡咯喹啉醌(PQQ)挽救表型后，将重新评估AIMS 1和AIMS 2的终点(AIMS 3)。这将是1)量化母亲肥胖引起的肾脏脂肪代谢的变化，2)确定母亲脂肪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的反应中的潜在作用，以及4)在怀孕和哺乳期间使用一种有效的抗氧化剂来挽救发育程序性“脂毒性”的第一项研究。这些研究的结果将为Jonscher博士未来的独立研究和对代谢性疾病传播机制的新见解提供新的蛋白质和代谢物靶标。