A novel treatment, TAT-HSP70, in attenuating lung injury in sepsis induced ARDS

一种新的治疗方法 TAT-HSP70 可减轻脓毒症引起的 ARDS 的肺损伤

基本信息

批准号：
7911484
负责人：
Mary Melanie Lyons
金额：
$ 4.14万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911484
关键词：
Activities of Daily Living Adenovirus Vector Adenoviruses Adult Respiratory Distress Syndrome Affect Attenuated Behavior Cause of Death Chimeric Proteins Critical Illness Critical Illness Polyneuropathy Development Disease Early Mobilizations Epithelial Cells Family Functional disorder HIV Heat-Shock Proteins 70 Heat-Shock Response Human Inflammation Injection of therapeutic agent Intensive Care Units Intervention Length of Stay Ligation Lung Mechanical ventilation Mission Motor Activity Muscle Nurses Organ Outcome Patients Proteins Puncture procedure Quality of life Recovery Research Research Training Rodent Model Role Scientist Sepsis Severities Survivors Syndrome System Therapeutic Therapeutic Agents Ventilator Weaning body system cell injury cell type disorder prevention improved lung injury mortality novel novel therapeutics public health relevance respiratory

项目摘要

DESCRIPTION (provided by applicant): The applicant seeks a research and training opportunity to successfully engage in understanding the role of a first of its kind novel therapeutic agent, Heat Shock Protein 70, in decreasing lung injury, decreasing mortality and increasing locomotor activity in a cecal ligation and double puncture (2CLP) rodent model of sepsis induced Acute Respiratory Distress Syndrome (ARDS). Sepsis, the leading cause of death in critically ill patients, is a syndrome of disordered inflammation with limited treatment options causing dysfunction in all organ systems. In survivors, recovery to resume activities of daily living is prolonged, profound and costly. Novel interventions that can eliminate the severity of organ dysfunction would be of immense value. The lung is the organ most affected by sepsis, with abnormalities taking the more severe form of ARDS. This is best treated with mechanical ventilation. However, use of exogenous respiratory support compounds immobility, muscular deconditioning, and critical illness polyneuropathy (CIP) that almost universally develop in patients with sepsis. Indeed, recent studies have shown that early mobilization of ARDS patients decreases intensive care unit and hospital length of stay. Thus, interventions that limit the extent of lung injury would provide both direct and indirect benefit. The commonly- used rodent model of sepsis 2CLP closely mimics many of the features of the human syndrome including sepsis, ARDS, sickness behavior, CIP, decreased locomotor activity, and difficulty in ventilator weaning. Sepsis causes dysfunction in a number of different types of cells, including pulmonary epithelial cells. One highly conserved endogenous mechanism that protects cells from injury is the Heat Shock Response (HSR) expressing HSPs. Our research focuses on the benefits of one specific family of HSPs, HSP70. 2CLP diminishes the expression of HSP70 in the lungs. This contributed significantly to increased lung injury consistent with ARDS and subsequently increased mortality. Augmentation of HSP70 expression using an adenovirus vector (AdHSP70) introduced into the lungs via tracheal injection significantly decreased lung injury and decreased mortality by 31%. Adenovirus therapy in humans may be problematic. Thus, strategies that enhance HSP70 abundance in pulmonary epithelial cells represent an under-explored therapeutic avenue. The applicant proposes an alternative delivery system, the use of a fusion protein (TAT-HSP70) that combines HSP70 with the HIV 1-TAT protein. We hypothesize three aims, that TAT-HSP70 will significantly attenuate lung injury and decrease mortality and further successful treatment with TAT-HSP70 will increase locomotor activity. These aims are consistent with NINR's mission statement of creating nurse scientists dedicated to conducting rigorous research generating new developments to improve outcomes of serious illness. PUBLIC HEALTH RELEVANCE: This proposal is a first of its kind, novel study of the role of HSP70 in decreasing lung injury, mortality and increasing locomotor activity in a sepsis induced Acute Respiratory Distress Syndrome rodent model. It evaluates a novel therapeutic agent for disease prevention, treatment, and improving patient quality of life.

描述（由申请人提供）：申请人寻求研究和培训机会，以成功地了解第一种新型治疗剂热休克蛋白 70 在减少肺损伤、降低死亡率和增加运动活性方面的作用。盲肠结扎和双穿刺（2CLP）败血症引起的急性呼吸窘迫综合征（ARDS）啮齿动物模型。脓毒症是危重患者死亡的主要原因，是一种炎症紊乱综合征，治疗选择有限，导致所有器官系统功能障碍。对于幸存者来说，恢复日常生活活动的时间较长、影响深远且成本高昂。能够消除器官功能障碍严重程度的新颖干预措施将具有巨大的价值。肺部是受脓毒症影响最严重的器官，异常情况会导致更严重的ARDS。最好通过机械通气来治疗。然而，使用外源性呼吸支持会导致脓毒症患者几乎普遍出现无法活动、肌肉失调和危重多发性神经病 (CIP)。事实上，最近的研究表明，ARDS 患者的早期活动可以减少重症监护病房和住院时间。因此，限制肺损伤程度的干预措施将提供直接和间接的益处。常用的脓毒症 2CLP 啮齿动物模型与人类综合征的许多特征非常相似，包括脓毒症、ARDS、病态行为、CIP、运动活动减少和呼吸机脱机困难。脓毒症导致许多不同类型的细胞功能障碍，包括肺上皮细胞。一种保护细胞免受损伤的高度保守的内源性机制是表达热休克反应（HSR）的热休克蛋白。我们的研究重点是 HSP70 这一特定家族的益处。 2CLP 减少肺部 HSP70 的表达。这显着增加了与 ARDS 一致的肺损伤，并随后增加了死亡率。使用通过气管注射引入肺部的腺病毒载体 (AdHSP70) 增强 HSP70 表达，可显着减少肺损伤，并将死亡率降低 31%。人类的腺病毒治疗可能存在问题。因此，增强肺上皮细胞中 HSP70 丰度的策略代表了一种尚未探索的治疗途径。申请人提出了一种替代递送系统，使用将HSP70与HIV 1-TAT蛋白结合的融合蛋白(TAT-HSP70)。我们假设三个目标，即 TAT-HSP70 将显着减轻肺损伤并降低死亡率，并且 TAT-HSP70 的进一步成功治疗将增加运动活动。这些目标与 NINR 的使命宣言是一致的，即培养护士科学家，致力于进行严格的研究，产生新的进展，以改善严重疾病的结果。公共健康相关性：本提案是首次针对 HSP70 在脓毒症引起的急性呼吸窘迫综合征啮齿动物模型中减少肺损伤、死亡率和增加运动活性方面的作用进行新研究。它评估一种用于疾病预防、治疗和改善患者生活质量的新型治疗剂。