Syndecan shedding after trauma and hemorrhagic shock

外伤和失血性休克后多配体脱落

• 批准号: 9067397
• 负责人: Rosemary A Kozar
• 金额: $ 29.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067397
• 关键词: Adhesions; Affect; Animal Model; Biology; Blood Vessels; Cell Culture Techniques; Cell surface; Cessation of life; Clinical; Coupled; Data; Development; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Epithelial Cells; Feasibility Studies; Foundations; Fresh Frozen Plasmas; Glycocalyx; Goals; Health; Hemorrhagic Shock; Heparitin Sulfate; Human; Image; In Vitro; Injury; Knockout Mice; Knowledge; Lead; Ligands; Link; Lung; Mediator of activation protein; Mission; Modeling; Molecular; Mus; Organ; Pathway interactions; Patients; Plasma; Play; Proteoglycan; Public Health; Research; Resuscitation; Role; Shock; Signal Transduction; Surface; TIMP3 gene; Testing; Time; Transfusion; Transgenic Mice; Trauma; Traumatic injury; Vertebral column; Work; adenoviral-mediated; base; burden of illness; cadherin 5; clinically relevant; fibroglycan; heparin proteoglycan; improved; improved outcome; in vivo; inhibitor/antagonist; injured; innovation; insight; lung injury; mortality; mouse model; mutant; novel; novel strategies; overexpression; receptor; reconstitution; repaired; restoration; syndecan

DESCRIPTION (provided by applicant): There is a fundamental gap in the understanding between syndecan-1 (sdc-1) shedding and mortality in severely injured patients in hemorrhagic shock (HS). Additionally, our knowledge of the precise cellular and molecular mechanisms responsible for reduced mortality by the early use of fresh frozen plasma (FFP) after HS is limited. While the long term goal is to understand the molecular link between HS-induced sdc-1 shedding and vascular instability, the objective of the current application is to identify how sdc- shedding contributes to vascular instability after HS and how shed sdc-1 is reconstituted by FFP. The central hypothesis is that 1) HS induces sdc-1 shedding from the endothelium; 2) sdc-1 shedding leads to vascular instability and organ injury; and 3) FFP based resuscitation repairs vascular instability and organ injury by restoring sdc-1 expression. This hypothesis is based on preliminary data which demonstrates the feasibility of studying syndecan biology in a model of HS. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Examine HS-induced sdc-1 ectodomain shedding and restitution; 2) Investigate the mechanism of sdc-1 shedding and restitution after HS; and 3) Investigate the specific contribution of endothelial syndecan-1 to restoration of vascular stability after HS. The approaches are innovative because they focus for the first time on shedding of sdc-1 after hemorrhagic shock and its restitution by FFP based resuscitationon. The proposed research is significant because it is expected to advance the understanding of HS-induced sdc-1 shedding and vascular hyperpermeability and to provide a mechanistic foundation to guide the use of FFP. The conclusions from this work are expected to not only help guide current therapies, but facilitate the development of novel strategies to reduce HS-related deaths after severe injury.

描述（由申请人提供）：在出血性休克（HS）中，Syndecan-1（SDC-1）脱落和死亡率之间的理解存在基本差距。此外，我们对通过在HS之后的早期使用新鲜冷冻血浆（FFP）的早期使用受到限制的精确细胞和分子机制的了解受到降低。尽管长期目标是了解HS诱导的SDC-1脱落与血管不稳定性之间的分子联系，但当前应用的目的是确定SDC脱落如何在HS后以及HS后的血管不稳定性以及如何通过FFP重构SDC-1。中心假设是1）HS诱导内皮中的SDC-1脱落； 2）SDC-1脱落会导致血管不稳定性和器官损伤； 3）基于FFP的复苏维修通过恢复SDC-1表达来维修血管不稳定性和器官损伤。该假设基于初步数据，该数据证明了在HS模型中研究Syndecan生物学的可行性。在强大的初步数据的指导下，将通过追求三个特定目的来检验该假设：1）检查HS诱导的SDC-1型e骨域的脱落和恢复； 2）研究HS后SDC-1脱落和恢复原状的机制； 3）研究内皮syndecan-1对HS后血管稳定性的恢复的特定贡献。这些方法具有创新性，因为它们首次将重点放在出血性冲击后SDC-1及其基于FFP的Resuscitationon恢复原状后的SDC-1。拟议的研究很重要，因为有望提高对HS诱导的SDC-1脱落和血管过敏性的理解，并提供机械基础来指导使用FFP。预计这项工作的结论不仅有助于指导当前的疗法，而且有助于制定新的策略，以减少严重受伤后与HS相关的死亡。

项目成果

Re: ADAM-17: A potential therapeutic target to prevent organ injury after hemorrhagic shock?

• DOI: 10.1097/ta.0000000000001397
• 发表时间: 2017-05
• 期刊: The journal of trauma and acute care surgery
• 作者: Kozar RA

Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock.

• DOI: 10.1371/journal.pone.0192363
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pati S;Peng Z;Wataha K;Miyazawa B;Potter DR;Kozar RA
• 通讯作者: Kozar RA

Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock.

• DOI: 10.1097/ta.0000000000001056
• 发表时间: 2016-08
• 期刊: The journal of trauma and acute care surgery
• 作者: Peng Z;Ban K;LeBlanc A;Kozar RA
• 通讯作者: Kozar RA

Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice.

• DOI: 10.1097/shk.0000000000000452
• 发表时间: 2015-11
• 期刊: Shock (Augusta, Ga.)
• 作者: Ban K;Peng Z;Pati S;Witkov RB;Park PW;Kozar RA
• 通讯作者: Kozar RA

Loss of Syndecan-1 Abrogates the Pulmonary Protective Phenotype Induced by Plasma After Hemorrhagic Shock.

• DOI: 10.1097/shk.0000000000000832
• 发表时间: 2017-09
• 期刊: Shock (Augusta, Ga.)
• 作者: Wu F;Peng Z;Park PW;Kozar RA
• 通讯作者: Kozar RA