The Role of SIRT5 in Regulating Cardiac Function and Metabolism

SIRT5 在调节心脏功能和代谢中的作用

• 批准号: 9264033
• 负责人: Kathleen Anne Hershberger
• 金额: $ 1.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264033
• 关键词: Affect; Animals; Basic Science; Biochemical; Biochemistry; Biological Assay; Cardiac; Cardiac health; Cell Respiration; Cellular Metabolic Process; Chemicals; Coupled; Data; Development; Diabetes Mellitus; Disease; Echocardiography; Enzymes; Family; Fostering; Functional disorder; Genotype; Goals; Health; Heart; Heart Diseases; Histology; Homeostasis; Hypertrophy; Impairment; Ketone Bodies; Knock-out; Knockout Mice; Knowledge; Lead; Lysine; Malignant Neoplasms; Measures; Mechanics; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Modification; Mus; National Heart, Lung, and Blood Institute; Outcome; Oxidoreductase; Pathway interactions; Physiological; Physiology; Pilot Projects; Post-Translational Protein Processing; Proteins; Proteomics; Public Health; Research; Research Design; Research Proposals; Role; Scientist; Sirtuins; Stress; Techniques; Testing; Therapeutic; Training; Work; base; beta-Hydroxybutyrate; constriction; heart function; heart metabolism; improved; insight; novel therapeutic intervention; oxidation; pressure; public health relevance; research and development; success

 DESCRIPTION (provided by applicant): The sirtuins are a family of NAD+-dependent deacylases that regulate metabolism and maintain metabolic homeostasis by removing chemical modifications from lysine residues of key metabolic enzymes. SIRT5 is located in the mitochondria and uniquely removes succinyl modifications from lysine residues. Recently a number of metabolic enzymes have been identified as regulated by SIRT5 mediated desuccinylation. However, the physiological significance of SIRT5 remains unknown. The long-term goal of this work is to better understand the crosstalk between cardiac function and metabolism and to ultimately identify novel therapeutic interventions to treat people with heart diseases. The objective of this research proposal is to characterize the effect of SIRT5 on cardiac function under basal and stressed conditions, and to identify specific proteins that are regulated by SIRT5. Based on preliminary data, the hypothesis guiding this work is that SIRT5 mediated desuccinylation regulates key pathways of oxidative metabolism and impaired SIRT5 function leads to metabolic inflexibility that affects cardiac function. The rationale for the proposed research is that the physiological role of SIRT5 is currently unknown, and identifying an effect of SIRT5 on cardiac function will establish a physiological role for SIRT5 via the mechanism of SIRT5 mediated desuccinylation. Guided by the preliminary data, the hypothesis will be tested by the following specific aims: 1) characterize the effect of SIRT5 on cardiac function; and 2) identify a mechanism by which SIRT5 regulates cardiac metabolism. In the first aim, heart function will be characterized in a SIRT5 knockout mouse under basal and stressed conditions using techniques of echocardiogram, pressure volume loop analysis, and histology. In the second aim, a specific enzyme will be identified and validated as a target of SIRT5 mediated desuccinylation using established biochemical assays. Based on preliminary data and the well-developed research design, this proposal holds a strong likelihood of scientific success. Further, the applicant has a high training potential based on a unique combination of classic scientific training in biochemistry coupled with current techniques in animal physiology and cardiac function research. The proposed research is significant because it is expected to lead to the identification of a physiological role for SIRT5 in regulating cardiac function and the identification of a metabolic mechanism for this role. Ultimately, this understanding will lead to deeper knowledge of cardiac metabolism and its relation to heart diseases in order to realize improved therapies for heart diseases.

 描述（由申请人提供）：sirtuins 是 NAD+ 依赖性脱酰酶家族，通过去除关键代谢酶的赖氨酸残基的化学修饰来调节代谢并维持代谢稳态。SIRT5 位于线粒体中，并且独特地去除赖氨酸残基的琥珀酰修饰。最近，许多代谢酶已被鉴定为受 SIRT5 介导的脱琥珀酰化调节，然而，其生理意义尚不清楚。 SIRT5 仍然未知。这项工作的长期目标是更好地了解心脏功能和代谢之间的相互作用，并最终确定治疗心脏病患者的新治疗干预措施。本研究提案的目的是表征 SIRT5 的效果。基础和应激条件下的心脏功能，并确定受 SIRT5 调节的特定蛋白质 根据初步数据，指导这项工作的假设是 SIRT5 介导的去琥珀酰化调节氧化代谢和受损的关键途径。 SIRT5 功能导致影响心脏功能的代谢不灵活，该研究的基本原理是 SIRT5 的生理作用目前尚不清楚，确定 SIRT5 对心脏功能的影响将通过 SIRT5 介导的机制确定 SIRT5 的生理作用。在初步数据的指导下，该假设将通过以下具体目标进行检验：1）表征 SIRT5 对心脏功能的影响；2）确定其机制。 SIRT5 调节心脏代谢。在第二个目标中，将使用超声心动图、压力容量环分析和组织学技术来表征 SIRT5 敲除小鼠在基础和应激条件下的心脏功能。根据初步数据和完善的研究设计，该提案被验证为 SIRT5 介导的脱琥珀酰化的目标。此外，申请人具有很高的培训潜力。这项研究将生物化学的经典科学训练与动物生理学和心脏功能研究的最新技术相结合，具有重要意义，因为它有望确定 SIRT5 在调节心脏功能中的生理作用，并确定 SIRT5 的功能。最终，这种理解将导致人们对心脏代谢及其与心脏病的关系有更深入的了解，从而改进心脏病的治疗方法。