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

• 批准号: 8032504
• 负责人: Mary Melanie Lyons
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8032504
• 关键词: Activities of Daily Living; Adenovirus Vector; Adenoviruses; Adult Respiratory Distress Syndrome; Affect; Animals; Attenuated; Behavior; Cause of Death; Cells; Chimeric Proteins; Critical Illness; Critical Illness Polyneuropathy; Data; Development; Disease; Dose; Early Mobilizations; Epithelial Cells; Family; Functional disorder; HIV; Heat shock proteins; Heat-Shock Proteins 70; Heat-Shock Response; Histologic; Hour; Human; Implant; Inflammation; Injection of therapeutic agent; Intensive Care Units; Interleukin-6; Intervention; Length of Stay; Ligation; Locomotion; Lung; Lung Inflammation; Mechanical ventilation; Mission; Molecular Weight; Motor Activity; Movement; Muscle; Nurses; Organ; Outcome; Patients; Pattern; Pilot Projects; Polyneuropathy; Proteins; Puncture procedure; Quality of life; Recovery; Research; Research Training; Rodent; Rodent Model; Role; Scientist; Sepsis; Series; Severities; Sprague-Dawley Rats; Stimulus; Structure of parenchyma of lung; Survivors; Syndrome; System; Testing; Therapeutic; Therapeutic Agents; Time; Trachea; Ventilator Weaning; body system; cell injury; cell type; disorder prevention; improved; lung injury; male; mortality; neutrophil; novel; novel therapeutic intervention; novel therapeutics; operation; polypeptide; pre-clinical; primary outcome; public health relevance; respiratory; response; secondary outcome; septic

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，以成功地了解同类新颖的治疗剂Head Heptar Protein 70在降低肺损伤，降低死亡率并增加肠结扎和双重刺激（2CLP）sepsis sepsis possirate at porce porce porce porce porcess arts Syndrome（ards ards Syndrome）中的作用。 败血症是重症患者死亡的主要原因，是一种炎症无序综合征，治疗方案有限，导致所有器官系统的功能障碍。在幸存者中，恢复恢复日常生活活动的延长，深刻和昂贵。可以消除器官功能障碍严重程度的新型干预措施将具有巨大的价值。肺是受败血症影响最大的器官，异常患者的ARD形式更为严重。最好通过机械通风处理。但是，使用外源呼吸支持可以使脓毒症患者几乎普遍发展的外源性呼吸支持化合物，肌肉解剖学和危重疾病多神经病（CIP）。实际上，最近的研究表明，早期动员ARDS患者会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。败血症2CLP的常用啮齿动物模型紧密地模拟了人类综合征的许多特征，包括败血症，ARDS，疾病行为，CIP，运动活性降低以及呼吸机断奶的难度。败血症会在许多不同类型的细胞（包括肺上皮细胞）中引起功能障碍。一种保护细胞免受损伤的高度保守的内源性机制是表达HSP的热休克反应（HSR）。我们的研究重点是HSP70的一个特定HSP家族的好处。 2CLP降低了HSP70在肺中的表达。这对与ARDS一致的肺损伤的增加显着贡献，并随后增加死亡率。使用腺病毒载体（ADHSP70）通过气管注射引入肺部的HSP70表达的增强表达，显着降低了肺损伤，死亡率降低了31％。人类腺病毒疗法可能是有问题的。因此，增强肺部上皮细胞中HSP70丰度的策略代表了探索的治疗途径。申请人提出了一种替代输送系统，即使用HSP70与HIV 1-TAT蛋白结合的融合蛋白（TAT-HSP70）的使用。我们假设三个目标，TAT-HSP70将显着减轻肺损伤并降低死亡率，并进一步成功治疗Tat-HSP70将增加运动活性。 这些目标与NINR的使命陈述是一致的，即创建致力于进行严格研究的护士科学家，从而产生新的发展以改善严重疾病的结果。 公共卫生相关性：该提案是对HSP70在降低肺损伤，死亡率和增加运动活性中的作用中的首个新型研究，在脓毒症引起的急性呼吸窘迫综合征啮齿动物模型中。它评估了一种新型的预防疾病，治疗和改善患者生活质量的治疗剂。