SUMO Conjugation and Deep Hypothermia-Induced Organ Protection

SUMO 结合和深低温诱导的器官保护

• 批准号: 8217294
• 负责人: WULF PASCHEN
• 金额: $ 38.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217294
• 关键词: Adult; Adverse effects; Age; Animals; Brain; Brain region; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular Surgical Procedures; Cardiovascular system; Cells; Cellular Stress; Cerebrum; Childhood; Clinical; Confocal Microscopy; Congenital Heart Defects; Exposure to; Heart Arrest; Hippocampus (Brain); Immunohistochemistry; Immunoprecipitation; Injury; Interruption; Ischemia; Kidney; Location; MicroRNAs; Nuclear Translocation; Operative Surgical Procedures; Organ; Outcome; Pathologic Processes; Pathway interactions; Patients; Perioperative; Play; Post-Translational Protein Processing; Procedures; Process; Proteins; Proteomics; Recovery; Research; Resistance; Risk; Role; Signal Transduction Pathway; Stroke; Subfamily lentivirinae; Sumoylation Pathway; Therapeutic; Therapeutic Intervention; Time; Ubiquitin; Vascular blood supply; Virus; Western Blotting; Work; cell injury; cellular transduction; design; genetically modified cells; glucose metabolism; induced hypothermia; interest; natural hypothermia; neonate; novel strategies; operation; protective effect; protein activation; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Various pediatric and adult cardiovascular operations involve cardiopulmonary bypass (CPB) procedures that require a period of circulatory arrest. Major cardiovascular surgery in pediatric and adult patients induces perioperative organ injury and is therefore associated with significant adverse cerebral, renal and cardiovascular outcomes. To protect organs from ischemic damage, surgery is usually performed during deep hypothermic conditions (deep hypothermic circulatory arrest, DHCA). Although the protective potential of deep hypothermia is unquestionable, little is known about the mechanisms through which it protects organs or how to maximize its efficacy. Elucidating the mechanisms underlying protection of organs by deep hypothermia is therefore of tremendous clinical interest. If we understood these mechanisms, we would be able to design therapeutic strategies to activate such processes and thus induce a state of tolerance without risking the adverse effects associated with deep hypothermia. We hypothesize that deep hypothermia protects organs from ischemic damage by activating the small ubiquitin-like modifier (SUMO) conjugation pathway. Protein sumoylation markedly influences the stability, localization and activity of transcription factors and other intracellular proteins. Deep hypothermia-induced changes in SUMO conjugation may therefore play a key role in defining the final outcome of cells exposed to transient DHCA. We found a marked increase in levels of SUMO conjugated proteins during deep hypothermia, and activation of SUMO conjugation has been shown to protect cells from damage induced by ischemia-like conditions. We have the following Specific Aims: 1) To examine the relationship between extent and duration of hypothermia and activation of the SUMO conjugation pathway; 2) To identify proteins in which SUMO conjugation is activated by hypothermia; 3) To verify whether by silencing SUMO expression and thus blocking deep hypothermia-induced activation of the SUMO conjugation pathway, it is possible to modify the sensitivity of organs to DHCA. It is widely believed that hypothermia-induced protection is a passive process whereby the rate of glucose metabolism is lowered and the time to terminal depolarization consequently increased. This would shorten the period of terminal depolarization and thus mitigate all pathological processes triggered during the state of energy depletion and manifested after recovery from ischemia. If our hypothesis proves valid, i.e. deep hypothermia does indeed induce an active process resulting in a rise in levels of SUMO conjugated proteins and activation of the SUMO conjugation pathway does play a key role in that process, it could revolutionize our understanding of the mechanisms underlying the protective effects of hypothermia. SUMO conjugation could represent an exciting new target for therapeutic intervention by providing a means of increasing the resistance of organs to a transient interruption of blood supply. PUBLIC HEALTH RELEVANCE: Circulatory arrest is required for various surgeries, including aortic surgery or correction of congenital heart defects in the neonates. To protect organs from damage caused by transient ischemia, circulatory arrest is carried out under deep hypothermic conditions. This proposal focuses on the hypothesis that activation of small ubiquitin-like modifier (SUMO) conjugation of target proteins plays a major role in deep hypothermiainduced organ protection. If our hypothesis proves valid, SUMO conjugation could prove to be a very exciting new target for therapeutic intervention by providing a means of increasing the resistance of organs to a transient interruption of blood supply.

描述（由申请人提供）：各种儿科和成人心血管手术涉及需要停循环一段时间的心肺转流（CPB）手术。儿科和成人患者的大心血管手术会引起围手术期器官损伤，因此与显著的不良脑、肾和心血管结局相关。为了保护器官免受缺血性损伤，手术通常在深低温条件下进行（深低温停循环，DHCA）。虽然深低温的保护潜力是毋庸置疑的，但人们对它保护器官的机制或如何最大限度地发挥其功效知之甚少。因此，阐明深低温保护器官的机制具有巨大的临床意义。如果我们了解这些机制，我们将能够设计治疗策略来激活这些过程，从而诱导耐受状态，而不会冒着与深度低温相关的不良反应。我们推测深低温通过激活小泛素样修饰物（SUMO）结合途径保护器官免受缺血性损伤。蛋白质类小泛素化显著影响转录因子和其他细胞内蛋白质的稳定性、定位和活性。因此，深度低氧诱导的SUMO结合的变化可能在定义暴露于瞬时DHCA的细胞的最终结果中发挥关键作用。我们发现在深低温期间SUMO结合蛋白的水平显著增加，并且SUMO结合的激活已显示出保护细胞免受缺血样条件诱导的损伤。我们有以下具体目的：1）检查低温的程度和持续时间与SUMO结合途径激活之间的关系; 2）鉴定 其中SUMO缀合被低温激活的蛋白; 3）为了验证是否通过沉默SUMO表达并因此阻断深度低温诱导的SUMO缀合途径的激活，可以改变器官对DHCA的敏感性。人们普遍认为，低血糖诱导的保护是一个被动的过程，其中葡萄糖代谢的速率降低，最终去极化的时间因此增加。这将缩短终末去极化的时间，从而减轻在能量耗尽状态期间触发并在缺血恢复后表现出的所有病理过程。如果我们的假设被证明是有效的，即深低温确实诱导了一个导致SUMO结合蛋白水平升高的活性过程，并且SUMO结合途径的激活在该过程中确实起着关键作用，那么它可能会彻底改变我们对低温保护作用机制的理解。SUMO缀合可以代表一个令人兴奋的新靶点，通过提供 一种增加器官对血液供应短暂中断的抵抗力的方法。 公共卫生相关性：各种手术都需要停循环，包括主动脉手术或新生儿先天性心脏病的矫正。为了保护器官免受短暂缺血引起的损伤，在深低温条件下进行循环停止。这一建议的重点是假设，激活小泛素样修饰物（SUMO）结合的靶蛋白发挥了重要作用，在深hypoxiainduced器官保护。如果我们的假设被证明是有效的，SUMO结合可以被证明是一个非常令人兴奋的新靶点，通过提供一种增加器官对短暂中断血液供应的抵抗力的方法来进行治疗干预。

项目成果

SUMO2/3 conjugation is an endogenous neuroprotective mechanism.

• DOI: 10.1038/jcbfm.2011.112
• 发表时间: 2011-11
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways.

• DOI: 10.1161/strokeaha.113.004315
• 发表时间: 2014-04
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Yang W;Sheng H;Thompson JW;Zhao S;Wang L;Miao P;Liu X;Moseley MA;Paschen W
• 通讯作者: Paschen W

Small ubiquitin-like modifier 1-3 conjugation [corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival.

• DOI: 10.1111/cas.12047
• 发表时间: 2013-01
• 期刊: Cancer science
• 影响因子: 5.7
• 作者: Yang W;Wang L;Roehn G;Pearlstein RD;Ali-Osman F;Pan H;Goldbrunner R;Krantz M;Harms C;Paschen W
• 通讯作者: Paschen W

Development of a high-throughput screening assay for inhibitors of small ubiquitin-like modifier proteases.

• DOI: 10.1177/1087057113479971
• 发表时间: 2013-06
• 期刊: Journal of biomolecular screening
• 作者: Yang W;Wang L;Paschen W
• 通讯作者: Paschen W

Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics.

• DOI: 10.1021/pr200834f
• 发表时间: 2012-02-03
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Yang W;Thompson JW;Wang Z;Wang L;Sheng H;Foster MW;Moseley MA;Paschen W
• 通讯作者: Paschen W