The Impact of Vasopressin on Mitochondrial Dysfunction in Hemorrhagic Shock

加压素对失血性休克线粒体功能障碍的影响

基本信息

批准号：
8280340
负责人：
Carrie Adelia Sims
金额：
$ 12.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8280340
关键词：
ATP Synthesis Pathway Accounting Animals Apoptosis Argipressin Biochemical Biochemistry Biological Assay Biophysics Biopsy Brattleboro Rats Cell Survival Cells Cessation of life Citric Acid Cycle Clinical Clinical Research Complement Complex Cytochrome c Reductase Cytochromes Data Defect Development Doctor of Philosophy Electrophoresis Event Functional disorder Goals Hemorrhagic Shock Hormonal Hormones Hospitals Human Hypotension In Vitro Injury Intensive Care Units Knock-out Knowledge Laboratories Laboratory Study Leukocytes Life Mediating Medicine Mentored Clinical Scientist Development Award (K08)Mentors Metabolism Mitochondria Modeling Morbidity - disease rate Muscle NADH Organ Oxidases Oxidative Phosphorylation Pathway interactions Patients Pennsylvania Phosphotransferases Physiological Play Post-Translational Protein Processing Protein Kinase C Proteome Rattus Reperfusion Therapy Replacement Therapy Research Research Project Grants Research Proposals Research Training Resolution Resuscitation Scientist Shock Signal Transduction Staging Supplementation Surgeon Techniques Testing Tissue Sample Trauma Universities Validation Vasoconstrictor Agents Vasopressins base biological systems career career development clinical practice complex IV education planning improved in vivo injured innovation mitochondrial dysfunction mortality novel polyacrylamide response translational approach trauma care

项目摘要

DESCRIPTION (provided by applicant): This application for a Mentored Clinical Scientist Development Award will investigate the development of mitochondrial dysfunction in late stage hemorrhagic shock and the potential benefit of vasopressin during resuscitation. The proposed research complements the mentors' biochemical, clinical and translational expertise and incorporates a formal education plan to complete a PhD in Biochemistry and Biophysics. PROJECT SUMMARY: Multiple organ dysfunction (MOD) remains the most common cause of in- hospital morbidity and mortality following traumatic injury. The underlying cellular events leading to MOD following hemorrhagic shock are uncertain, but impaired mitochondrial function has been strongly implicated. Recently, the hormone arginine vasopressin (AVP) has been investigated as an adjunct during the resuscitation of severe trauma. In addition to its vasopressor qualities, AVP may be important in thwarting the development of MOD following trauma by modulating the formation of NADH, activating mitochondrial ATP synthesis and inhibiting apoptosis. Based on preliminary data, we hypothesize that hemorrhagic shock results in modifiable defects in mitochondrial function that can be mitigated by supplementing AVP during resuscitation. This hypothesis will be tested in vivo using a naturally occurring AVP-knockout (i.e. Brattleboro rat) and ex-vivo using tissue samples from injured trauma patients. This unique translational approach seeks to understand how cellular pathways influence biological systems and ultimately impact the care of the trauma patient. Specifically, this research proposal will: 1) investigate the mechanism by which AVP provides mitochondrial protection (e.g. via Ca2+ signaling vs. kinase mediated complex subunit hyperphosphorylation), 2) determine if AVP supplementation during resuscitation decreases organ dysfunction, and 3) assess the impact of AVP on the mitochondrial function in tissue samples from severely injured patient. In addition to traditional techniques used to assess mitochondrial function, our use of Blue Native polyacrylamide electrophoresis provides an unprecedented opportunity to explore the mitochondrial proteome and post- translational modifications following shock. The proposed project is innovative because although AVP has been used as a vasopressor during resuscitation, its beneficial impact on mitochondrial metabolism has only been explored in vitro. Moreover, rigorous scientific validation supporting the use AVP during resuscitation has the potential to dramatically alter routine clinical practice. PROJECT RELEVANCE: The knowledge gained from this proposal will contribute to the development of innovative, life-saving resuscitative strategies by providing a deeper understanding of how shock-induced mitochondrial dysfunction progresses to MOD.

描述（由申请人提供）：该指导的临床科学家发展奖的申请将调查线粒体功能障碍在晚期出血性休克中的发展，以及在复苏期间加压素的潜在益处。拟议的研究补充了导师的生化，临床和翻译专业知识，并纳入了正规教育计划，以完成生物化学和生物物理学博士学位。项目摘要：多发性器官功能障碍（MOD）仍然是创伤后医院发病率和死亡率的最常见原因。导致MOD后出血性休克导致MOD的基础事件尚不确定，但是线粒体功能受损已被严重牵涉。最近，在严重创伤复苏期间，已研究了激素精氨酸加压素（AVP）。除了其加压剂质量外，AVP还可以通过调节NADH的形成，激活线粒体ATP合成并抑制凋亡来挫败MOD的发展。根据初步数据，我们假设出血性休克会导致线粒体功能的可修改缺陷，从而可以通过补充复苏期间补充AVP来减轻。该假设将在体内使用天然存在的AVP敲除（即Brattleboro大鼠）和前体内使用受伤创伤患者的组织样品进行检验。这种独特的翻译方法旨在了解细胞途径如何影响生物系统，并最终影响创伤患者的护理。具体而言，该研究建议将：1）研究AVP提供线粒体保护的机制（例如，通过Ca2+信号传导与激酶介导的复杂亚基过度磷酸化），2）确定恢复过程中补充AVP是否会降低器官功能障碍的降低，以及3）评估AVP对甲状腺粒粒细胞的影响，并评估AVP对线粒体核对层的影响。除了用于评估线粒体功能的传统技术外，我们对蓝色天然聚丙烯酰胺电泳的使用还为探索线粒体蛋白质组和冲击后翻译后修饰提供了前所未有的机会。该提出的项目具有创新性，因为尽管AVP在复苏期间已被用作加压剂，但其对线粒体代谢的有益影响仅在体外探索。此外，在复苏期间支持使用AVP的严格科学验证有可能极大地改变常规临床实践。项目相关性：通过这项提案所获得的知识将有助于通过对震动引起的线粒体功能障碍如何发展为MOD的创新，挽救生命的复苏策略的发展。