The Evaluation of TLT-1 as treatment for ALI/ARDS

TLT-1治疗ALI/ARDS的评价

基本信息

批准号：
9450382
负责人：
Jessica Morales-Ortiz
金额：
$ 1.89万
依托单位：
UNIVERSITY OF PUERTO RICO RIO PIEDRAS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-13 至 2018-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9450382
关键词：
Accounting Actins Acute Acute Lung Injury Adult Respiratory Distress Syndrome Alpha Granule Alveolitis Antibodies Attenuated Binding Biological Process Blood Blood Platelets Cell Communication Cells Clinical Clinical Trials Coronary Arteriosclerosis Cytoplasmic Granules Data Development Disease Disease Management Dissection Edema Endothelial Cells Endothelium Evaluation Exhibits Fluorescein-5-isothiocyanate Functional disorder Healthcare Hemorrhage Hemostatic Agents Hemostatic function Immune response Immune system Incubated Inflammation Inflammatory Inflammatory Response Knockout Mice Knowledge Label Laboratory Study Lead Leukocytes Life Link Lipopolysaccharides Lung Lung Inflammation Lung diseases Maintenance Mediating Mediation Medical Megakaryocytes Membrane Modeling Molecular Mus Myeloid Cells P-Selectin Pathology Patients Phenotype Property Proteins Proto-Oncogene Proteins c-akt Publishing Pulmonary Edema Reaction Recombinants Reporting Research Respiratory Failure Role Selectins Signal Transduction Site Testing Therapeutic Therapeutic Effect Transcript Trauma patient Vasculitis Work alternative treatment base controlled release cost economic impact immunoregulation in vivo interest mortality mouse model neutrophil novel therapeutic intervention novel therapeutics polymerization prevent receptor response septic patients targeted treatment tool

Accounting Actins Acute Acute Lung Injury Adult Respiratory Distress Syndrome Alpha Granule Alveolitis Antibodies Attenuated Binding Biological Process Blood Blood Platelets Cell Communication Cells Clinical Clinical Trials Coronary Arteriosclerosis Cytoplasmic Granules Data Development Disease Disease Management Dissection Edema Endothelial Cells Endothelium Evaluation Exhibits Fluorescein-5-isothiocyanate Functional disorder Healthcare Hemorrhage Hemostatic Agents Hemostatic function Immune response Immune system Incubated Inflammation Inflammatory Inflammatory Response Knockout Mice Knowledge Label Laboratory Study Lead Leukocytes Life Link Lipopolysaccharides Lung Lung Inflammation Lung diseases Maintenance Mediating Mediation Medical Megakaryocytes Membrane Modeling Molecular Mus Myeloid Cells P-Selectin Pathology Patients Phenotype Property Proteins Proto-Oncogene Proteins c-akt Publishing Pulmonary Edema Reaction Recombinants Reporting Research Respiratory Failure Role Selectins Signal Transduction Site Testing Therapeutic Therapeutic Effect Transcript Trauma patient Vasculitis Work alternative treatment base controlled release cost economic impact immunoregulation in vivo interest mortality mouse model neutrophil novel therapeutic intervention novel therapeutics polymerization prevent receptor response septic patients targeted treatment tool

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项目摘要

Project Summary Acute Lung injury especially acute respiratory distress syndrome (ARDS) have been identified as life threatening conditions associated with significant mortality rate. Despite advances in the past decades in the knowledge on lung diseases, ARDS continues to claim the lives of more than 40% of its victims. The increase in health care associated costs has a major economic impact, while major clinical efforts to manage this disease are insufficient due to an uncomplete understanding of the mechanisms that control the pathology manifestations. Blood platelets, neutrophils and endothelial cells have been identified as the key components in the progression of ALI/ARDS. Moreover, our understanding of platelets function has shifted over the past years from a simple hemostatic tool to dynamic modulators of the immune response. The current paradigm of platelets intents to uncover the molecular mechanisms that make these cells major orchestrators of inflammation. Previous reports have demonstrated that the absence of platelets leads to increase endothelial damage, aberrant neutrophil function and hemorrhage during inflammation. Moreover, these effects have been shown to be controlled by the release of platelet granules during activation. To date, the identity of the platelet granule molecule or molecules involved in this remains to be elucidated representing gab in our knowledge. Accordingly, this study seeks to identify key platelet components that modulate systemic response during inflammation through the modulation of neutrophil-endothelial cell crosstalk and mechanisms involved. To dissect that question we will evaluate a platelet granule product known as TLT-1 in the mediation of the signaling mechanisms that modulates neutrophil -endothelial cell cross-talk during inflammation. The basis for the selection of TLT-1 as a potential target emerges from previous studies that demonstrated that TLT-1 knockout mice exhibited increased edema and hemorrhage together with a marked dysfunction of neutrophils during inflammation elicited by the Schwartzman reaction derived vasculitis. Moreover, we have evaluated TLT-1 functions in other models of inflammation including a mouse model of ALI using intranasal inoculation of LPS. Our preliminary data shows that TLT-1 prevents inflammatory associated hemorrhage while facilitate neutrophils transmigration in lung leading to decrease endothelial damage. Therefore, based on these previous observations we hypothesize that TLT-1 mediates the signaling mechanisms that regulate neutrophil capacity to transmigrate to the inflammatory site and modulate neutrophil- endothelial cell interactions during inflammation and therefore controlling the immune response. We developed two specific aims to answer that question. The aims are as follows: (i) Define a role for TLT-1 in platelet-neutrophill-endothelial cell interactions during inflammation and (ii) Elucidate the therapeutic effects of TLT-1 on ALI/ARDS. This two aims will help to fulfill our current understanding of platelet biological functions in inflammation. The answers obtained through the realization of this research work will empower our knowledge to be able to develop new alternative treatments directed to control systemic response to inflammation.

项目摘要急性肺损伤，尤其是急性呼吸窘迫综合征（ARDS）已被确定为生命威胁与死亡率显着相关的条件。尽管过去的进步在有关肺部疾病的知识中，ARDS继续夺取超过40％的生命它的受害者。医疗保健相关成本的增加具有重大的经济影响，而主要由于对这种疾病的管理临床努力不足，因为对控制病理表现的机制。血小板，中性粒细胞和内皮细胞已被确定为ALI/ARDS进展中的关键成分。而且，我们的在过去的几年中，对血小板功能的了解已从简单的止血工具转变为免疫反应的动态调节剂。当前的血小板范式旨在发现使这些细胞主要的炎症编排的分子机制。以前的报告表明，缺乏血小板会导致内皮损害增加，炎症期间异常的中性粒细胞功能和出血。而且，这些影响一直是被激活过程中血小板颗粒的释放所控制。迄今为止，与此相关的血小板颗粒分子或分子剩余的分子尚待阐明代表GAB 我们的知识。因此，本研究旨在识别调节的关键血小板组件通过调节中性粒细胞 - 内皮细胞串扰，在炎症过程中的全身反应和涉及的机制。为了剖析这个问题，我们将评估已知的血小板颗粒产品作为调节中性粒细胞细胞的信号传导机制中的TLT -1 炎症期间的串扰。选择TLT-1作为潜在目标的基础从以前的研究表明，TLT-1敲除小鼠表现出增加的水肿和在炎症过程中引起的炎症期间出血以及明显的中性粒细胞功能障碍 Schwartzman反应衍生出血管炎。此外，我们已经评估了其他的TLT-1功能炎症模型，包括使用LPS内鼻内接种的ALI小鼠模型。我们的初步数据表明，TLT-1可以防止炎症相关的出血，同时促进中性粒细胞在肺中转移，导致内皮损害减少。因此，基于这些先前的观察结果我们假设TLT-1介导了信号传导机制调节嗜中性粒细胞的能力以移民到炎症部位并调节中性粒细胞炎症过程中的内皮细胞相互作用，因此控制免疫反应。我们开发了两个具体的目的，以回答这个问题。目的如下：（i）定义一个角色在炎症期间，血小板中性卵石 - 层状细胞相互作用的TLT-1和（ii）阐明 TLT-1对ALI/ARDS的治疗作用。这两个目标将有助于实现我们的当前了解炎症中血小板生物学功能。通过实现这项研究工作将使我们的知识能够开发新的替代方案致力于控制炎症的全身反应的治疗方法。