Sepsis Induced Immune Cell Death and Multiple Organ Failure

脓毒症引起的免疫细胞死亡和多器官衰竭

基本信息

批准号：
8102732
负责人：
Jared Thomas Muenzer
金额：
$ 10.74万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-18 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Septic shock and the resultant multiple organ failure it induces is the leading cause of death in most intensive care units in the United States. Over 750,000 people become septic each year with a mortality rate of 30-40% and an approximate cost of $16.7 billion. Many studies in animal models and in patients who have died of sepsis have shown that sepsis induces extensive loss of white blood cells via apoptosis. This immune cell loss likely compromises the host's ability to fight infection and increases the risk of death from new infections. In addition, there are now multiple studies showing that uptake of apoptotic cells by macrophages and other phagocytic cells suppresses their ability to fight infection and contributes to immunosuppression. Furthermore, several studies in animal models of sepsis have shown that blocking apoptosis of lymphocytes improves overall survival. The Bcl-2 family of proteins have been shown to play a critical role in sepsis-induced lymphocyte apoptosis. Recently, over-expression of anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL) or deletion of pro-apoptotic family members (Bim, Bid, and Puma) has been shown to decrease immune effector cell apoptosis and increase survival in animal models of sepsis. Preliminary work in our lab has shown that reduction of Bim expression using siRNA causes a dramatic decrease in sepsis-induced lymphocyte apoptosis and thus offers the potential to recapitulate the genetic deletion. The guiding hypothesis of the present proposal is that siRNA-mediated reduction of expression of pro-apoptotic Bcl-2 family members will prevent sepsis-induced apoptosis, ameliorate the sepsis-induced immune suppression, and improve survival. In addition, the molecular mechanisms and pathways of apoptotic cell death in sepsis will be examined using siRNA directed therapy. Finally, mice possessing a "humanized" immune system will be studied to determine the potential efficacy of siRNA therapy in a clinically relevant, translational model of sepsis.

描述（由申请人提供）：IT引起的败血性休克和由此产生的多器官衰竭是美国大多数重症监护病房的主要死亡原因。每年有超过75万人成为中毒，死亡率为30-40％，大约成本为167亿美元。动物模型和死于败血症的患者的许多研究表明，败血症通过凋亡诱导白细胞的广泛丧失。这种免疫细胞损失可能损害了宿主对抗感染的能力，并增加了新感染的死亡风险。此外，现在有多项研究表明，巨噬细胞和其他吞噬细胞对凋亡细胞的吸收会抑制其对抗感染的能力，并有助于免疫抑制。此外，在败血症动物模型中进行了一些研究表明，阻断淋巴细胞凋亡可提高总体生存率。 BCL-2蛋白质家族已显示在败血症诱导的淋巴细胞凋亡中起关键作用。最近，抗凋亡BCL-2家族成员（BCL-2，BCL-XL）或促凋亡家族成员的缺失（BIM，BIM和PUMA）已被证明可降低免疫效应细胞凋亡并增加脓毒症动物模型中的抗害者细胞凋亡并增加生存率。我们实验室中的初步工作表明，使用siRNA降低BIM表达会导致败血症诱导的淋巴细胞凋亡急剧减少，因此提供了概括遗传缺失的潜力。本提案的指导假设是siRNA介导的促凋亡Bcl-2家族成员的表达降低将防止败血症诱导的细胞凋亡，改善败血症诱导的免疫抑制并提高生存率。另外，将使用siRNA定向治疗检查败血症中凋亡细胞死亡的分子机制和途径。最后，将研究具有“人性化”免疫系统的小鼠，以确定siRNA治疗在脓毒症的临床相关，翻译模型中的潜在疗效。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased susceptibility to Candida infection following cecal ligation and puncture.

DOI：
10.1016/j.bbrc.2011.09.017
发表时间：
2011-10-14
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Davis, Christopher G.;Chang, Kathy;Osborne, Dale;Walton, Andrew H.;Dunne, W. Michael;Muenzer, Jared T.
通讯作者：
Muenzer, Jared T.

Evaluation of the precision of emergency department diagnoses in young children with fever.

幼儿发热急诊诊断准确率评价

DOI：
10.1177/0009922811417295
发表时间：
2012
期刊：
Clinical pediatrics
影响因子：
1.6
作者：
Colvin,JoshuaM;Jaffe,DavidM;Muenzer,JaredT
通讯作者：
Muenzer,JaredT

Preliminary evidence for leukocyte transcriptional signatures for pediatric ventilator-associated pneumonia.

儿科呼吸机相关肺炎白细胞转录特征的初步证据。

DOI：
10.1177/0885066611406835
发表时间：
2012
期刊：
Journal of intensive care medicine
影响因子：
3.1
作者：
Werner,JasonA;Schierding,William;Dixon,David;MacMillan,Sandra;Oppedal,Douglas;Muenzer,Jared;Cobb,JPerren;Checchia,PaulA
通讯作者：
Checchia,PaulA