A Biohybrid Device for Regulating Inflammation in Sepsis

调节脓毒症炎症的生物混合装置

基本信息

批准号：
8818081
负责人：
JOERG C. GERLACH
金额：
$ 34.65万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818081
关键词：
Accounting Acute Anti-Inflammatory Agents Anti-inflammatory Attenuated Bioreactors Blood Circulation CCL2 gene CXCL1 gene Cells Cessation of life Chronic Clinical Trials Computer Simulation Data Dendritic Cells Devices Diagnosis Disease Endotoxins Feedback Free Radicals Functional disorder Gene-Modified Goals HepG2 Hepatocyte Human Immune In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Injury Lead Lipids Medical Device Methodology Molecular Organ Patients Pattern Process Production Rattus Reaction Regulation Resolution Sepsis Solid Solutions Stimulus Stress System TNF gene Testing Text Therapeutic Time Tissues Trauma Tumor Necrosis Factor-alpha Work abstracting base biological adaptation to stress cell injury chemokine clinical efficacy computer based statistical methods cost cytokine experience in vitro Model in vivo inhibitor/antagonist insight novel novel strategies pathogen promoter receptor research study septic stressor

项目摘要

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Sepsis accounts for nearly 10% of total U.S. deaths, costing nearly $17 billion. Sepsis induces an acute inflammatory response. Properly-regulated inflammation allows for recognition and reaction to injury or infection, but inadequate or overly-robust inflammation can lead to multiple organ dysfunction and death. We propose that acute inflammation in sepsis may evolve too rapidly to be modulated appropriately, and suggest that therapies should focus not on abolishing inflammation, but rather on attenuating self-sustaining inflammation. Based on a combination of experiments and computational modeling, we propose a self- regulating device for patient-specific, adaptive regulation of inflammation. Our device, seeded with genetically- modified human HepG2 hepatocytes, has already been tested both in vitro and in endotoxemic and septic rats. We propose to create a novel class of biohybrid devices for regulating inflammation in sepsis using an iterative process of computational simulations combined with in vitro and in vivo studies (Aim 1), and to define the impact of the circulating inflammatory milieu on the HepG2 cells in the biohybrid device (Aim 2). We will optimize the molecular composition, timing, and duration of bioreactor-based delivery of sTNFR – driven constitutively or in an adaptive fashion as inferred from preliminary computational modeling. These studies will be carried out iteratively with computational modeling of the disease and the impact of the biohybrid devices on the disease in the context of in silico clinical trials, in order to predict the likelihood of clinical efficacy of this transformative class of medical device. Furthermore, we will define in vitro the inflammatory and stress responses of HepG2 cells subjected to the extracorporeal inflammatory milieu they will encounter in the context of our studies, and utilize these data to optimize in vivo bioreactor conditions and to revise in silico clinical trials. This approach represents a novel strategy for rational reprogramming of acute inflammation in sepsis, with potential impact on other acute inflammatory diseases.

此处输入的文本是您的申请的新摘要信息。此部分不得再存在。超过 30 行文本。败血症占美国总死亡人数的近 10%，败血症引起的急性疾病造成的损失近 170 亿美元。适当调节炎症可以识别损伤或做出反应。感染，但炎症不足或过度强烈可能导致多器官功能障碍和死亡。提出脓毒症中的急性炎症可能发展得太快而无法适当调节，并建议治疗不应侧重于消除炎症，而应侧重于减弱自我维持基于实验和计算模型的结合，我们提出了一种自我炎症。用于患者特异性、适应性炎症调节的调节装置我们的装置植入了基因- 改良的人 HepG2 肝细胞已在体外以及内毒素血症和脓毒症大鼠中进行了测试。我们建议创建一类新型生物混合装置，用于使用迭代调节脓毒症中的炎症计算模拟与体外和体内研究相结合的过程（目标 1），并定义循环炎症环境对生物混合装置中 HepG2 细胞的影响（目标 2）。优化基于生物反应器的 sTNFR 驱动的分子组成、时间安排和持续时间这些研究将本构地或以适应性方式从初步计算模型中推断出来。通过疾病的计算模型以及生物混合设备对疾病的影响迭代进行在计算机临床试验的背景下研究该疾病，以预测该疾病临床疗效的可能性此外，我们将在体外定义炎症和压力。 HepG2 细胞对体外炎症环境的反应我们的研究背景，并利用这些数据来优化体内生物反应器条件并进行计算机修正这种方法代表了一种对急性炎症进行合理重编程的新策略。败血症，对其他急性炎症性疾病有潜在影响。