The immunomodulatory effects of extracellular Hsp70

细胞外Hsp70的免疫调节作用

基本信息

批准号：
7796848
负责人：
DEREK S WHEELER
金额：
$ 12.1万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7796848
关键词：
Acids Address Attention Biochemical Cardiopulmonary Bypass Carrier Proteins Cell Line Cell Survival Cells Cellular Stress Child Clinical Complement Endothelial Cells Endotoxins Epithelial Exposure to Family Gene Deletion Genetic Programming Goals Gram-Positive Bacteria Heat shock proteins Heat-Shock Proteins 70 Homeostasis Human Immune response In Vitro Injury Kinetics Laboratories Life Ligation Link Lipopolysaccharides Macrophage Activation Modeling Molecular Chaperones Mononuclear Mus Natural Immunity Necrosis Nuclear Organ Outcome Pathway interactions Peptidoglycan Peritoneal Macrophages Peritonitis Play Process Protein Binding Puncture procedure Research Research Personnel Resistance Role Sepsis Septic Shock Serum Signal Transduction Signal Transduction Pathway Stimulus Stress TLR4 gene Techniques Testing Tissues Toll-Like Receptor 2 Trauma Work clinically relevant cytokine extracellular in vivo insight macrophage member monocyte novel preconditioning programs protein function protein misfolding receptor research study response stress tolerance

项目摘要

During steady-state conditions, heat shock proteins (HSPs) function in the intracellular compartment as molecular chaperones, assisting with the assembly, stabilization, folding, and transport of proteins. Under conditions of stress, HSPs bind and stabilize misfolded proteins and protect them from denaturation, thereby conferring resistance to further stress, an effect known as "stress tolerance." Recent evidence has focused attention on the role that extracellular HSPs play in the host innate immune response as opposed to their more commonly ascribed intracellular chaperone functions. For example, extracellular Hsp70, a member of the 70 kDa family of HSPs plays an important immuno-modulatory role, serving as both a chaperone and cytokine ("chaperokine"). This new paradigm may be explained by the so-called "danger hypothesis", in which stressed cells release Hsp70 into their surrounding extracellular milieu to signal an impending "danger" to neighboring cells. We have shown that stressed monocytes andmacrophages release functional Hsp70 in vitro and that extracellular Hsp70 correlates with poor outcome in children with septic shock. Several questions, however, remain unanswered. Our goals are to further elucidate the mechanisms leading to the extracellular release of Hsp70 and to understand the functional role of extracellular Hsp70 in vitro and in vivo. Accordingly, the central hypothesis of the current proposal is that extracellular Hsp70 modulates important proinflammatory signal transduction pathways in vitro and in vivo. Using a variety of techniques and models, we will determine the conditions and mechanisms leading to release of Hsp70 in vitro and in vivo (Specific Aim 1), determine the effect of extracellular Hsp70 on the innate immune response to components of both gram negative and gram positive bacteria in vitro and in vivo (Specific Aims 2, 3), and determine the effects of extracellular Hsp70 on the innate immune response to polymicrobial sepsis in vivo (Specific Aim 4). The novel finding that an endogenous molecule such as Hsp70 could modulate the host response to a variety of stimuli acting via multiple receptor pathways would provide important insight regarding the functional role of extracellular HSP70 and could ultimately provide a mechanistic link between tissue injury and modulation of the host innate immune response in clinical conditions such as trauma, sepsis, and MODS.

在稳态条件下，热激蛋白（HSP）在细胞内室中的功能分子伴侣，辅助组装，稳定，折叠和蛋白质运输。在下面 HSP的压力条件结合并稳定错误折叠的蛋白质并保护它们免受变性，从而赋予对进一步压力的抵抗力，这种效果称为“应激耐受性”。最近的证据有将注意力集中在细胞外HSP在宿主先天免疫反应中的作用对于他们更常见的细胞内伴侣函数。例如，细胞外Hsp70，a 70 KDA HSP家族的成员扮演着重要的免疫调节作用，既是伴侣和细胞因子（“伴侣”）。这种新范式可以用所谓的“危险”来解释假设”，其中压力细胞将HSP70释放到周围的细胞外环境中，以信号即将对邻近细胞的“危险”。我们已经证明了压力的单核细胞和巨噬细胞在体外释放功能性HSP70，并且细胞外HSP70与患有儿童的结果不佳败血性冲击。但是，几个问题仍未得到答复。我们的目标是进一步阐明导致HSP70细胞外释放的机制，并了解细胞外HSP70体外和体内。因此，当前提议的核心假设是细胞外HSP70在体外和体内调节重要的促炎信号转导途径。使用各种技术和模型，我们将确定导致的条件和机制 HSP70在体外和体内的释放（特定目标1），确定细胞外HSP70对对革兰氏阴性和革兰氏阳性细菌的成分的先天免疫反应在体外和中体内（特定目标2，3），并确定细胞外Hsp70对先天免疫反应的影响体内多数败血症（特定目标4）。新颖的发现，例如内源分子 HSP70可以通过多个受体途径调节对各种刺激作用的宿主反应提供有关细胞外HSP70功能作用的重要见解，并最终可以提供临床中宿主先天免疫反应的组织损伤与调节之间的机械联系创伤，败血症和mod等条件。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sepsis in the pediatric cardiac intensive care unit.

儿科心脏重症监护病房的脓毒症。

DOI：
10.1177/2150135111403781
发表时间：
2011
期刊：
World journal for pediatric & congenital heart surgery
影响因子：
0.9
作者：
Wheeler,DerekS;Jeffries,HowardE;Zimmerman,JerryJ;Wong,HectorR;Carcillo,JosephA
通讯作者：
Carcillo,JosephA

Approaches to the Management of Acute Kidney Injury in Children.