权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Stabilization of gap/tight junctions to ameliorate brain death induced endothelial cell injury

间隙/紧密连接的稳定以改善脑死亡引起的内皮细胞损伤

基本信息

批准号：
9141772
负责人：
Gautam Sudhir Ghatnekar
金额：
$ 22.5万
依托单位：
XEQUEL BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-04 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9141772
关键词：
Acute Affect Allogenic Animals Biodistribution Biological Assay Biological Preservation Blood Vessels Brain Death Cell Adhesion Molecules Cells Cellular Stress Cicatrix Clinical Clinical Data Coagulation Process Coculture Techniques Communication Cryopreservation Data Endothelial Cells Enzyme-Linked Immunosorbent Assay Event Fibroblasts Flow Cytometry Gap Junctions Goals Graft Rejection Grant Half-Life Healed Health Heart Heart Diseases Heart Injuries Heart Transplantation Immune Immunosuppression Infiltration Inflammation Inflammatory Response Injury Intercellular Junctions Ischemia Kidney Lead Leukocytes Liver Living Donors Lung Measurement Measures Metabolic Migration Assay Modeling Mus Organ Organ Donations Organ Donor Organ Preservation Organ Preservation Solutions Organ Transplantation Organ Viability Outcome Peptides Peripheral Permeability Pharmacotherapy Phase Physiological Play Reperfusion Injury Reperfusion Therapy Research Resistance Rodent Safety Small Business Innovation Research Grant Source Staging Survival Rate T-Lymphocyte Testing Therapeutic Thrombosis Tight Junctions Time Transplantation Treatment Efficacy Up-Regulation adaptive immunity base cell injury chronic wound clinically relevant cytokine efficacy testing endothelial dysfunction graft failure healing immunogenicity implantation improved improved outcome in vitro Model in vivo migration novel novel strategies phase 1 study preclinical study prevent public health relevance regenerative response success wound

项目摘要

DESCRIPTION (provided by applicant): Transplantation is a widely accepted and highly successful therapy for end-stage heart disease. While success rates and survival have risen steadily since its inception almost 50 years ago, due largely to improved immunosuppression regimes, there is a growing appreciate that factors associated with brain death, organ donation, procurement and storage, prior to implantation greatly effect outcomes post transplantation. Clinical data has demonstrated that recipients of hearts from living donors have significantly improved outcomes as compared to those from cadaveric sources. These data suggest that insults to the donor organ induced by brain death, and cold storage, predispose to poorer post transplantation outcomes. These injurious events are thought to initiate organ injury, endothelial dysfunction, and inflammation that are further exacerbated upon implantation and reperfusion, and that primes the donor organ for alloimmune recognition. Therefore strategies to minimize or switch off these injurious events are likely to improve graft outcomes. Cold preservation has greatly facilitated the use of cadaveric hearts for transplantation but, clearly, damage occurs prior to storage from brain death, and during both the preservation episode and the reperfusion phase. While metabolic additives have been incorporated into preservation solutions to prolong storage times and improve organ viability no additives have been incorporated into the preservation solutions to minimize endothelial injury/activation. We hypothesize that brain death, cold preservation, and ischemia reperfusion injury induces cell junction damage, which leads to inflammation, heart damage, and endothelial dysfunction upon reperfusion, and that inclusion of a novel gap and tight junction stabilizing peptide, ACT1, would preserve cell junctions during cold preservation and reduce graft damage and immunogenicity upon reperfusion.

描述(申请人提供)：移植是一种被广泛接受且非常成功的终末期心脏病治疗方法。自近50年前建立以来，移植成功率和存活率稳步上升，这主要是由于免疫抑制制度的改进，但越来越多的人认识到，与脑死亡、器官捐赠、移植前的采购和储存相关的因素对移植后的预后有很大影响。临床数据表明，与来自身体来源的心脏相比，来自活体捐赠者的心脏接受者的预后显著改善。这些数据表明，脑死亡和冷藏对供者器官的侮辱，容易导致移植后较差的结果。这些损害性事件被认为引发器官损伤、内皮功能障碍和炎症，在植入和再灌注后进一步加剧，并为供体器官的同种免疫识别做好准备。因此，尽量减少或关闭这些有害事件的策略可能会改善移植物的结果。冷保存极大地促进了身体心脏用于移植，但显然，损伤发生在脑死亡保存之前，以及保存期间和再灌注期。虽然代谢性添加剂已被加入到保存液中以延长保存时间和提高器官存活率，但没有任何添加剂被添加到保存液中以将内皮损伤/激活降至最低。我们假设脑死亡、冷保存和缺血再灌注损伤导致细胞连接损伤，从而导致再灌注时的炎症、心脏损伤和内皮功能障碍，而加入一种新的缝隙和紧密连接稳定肽ACT1将在冷保存期间保护细胞连接，减少再灌注时的移植物损伤和免疫原性。