The role of Mal in Toll-like receptor signal transduction of the pro-inflammatory response.

脓毒症每年导致的死亡人数超过乳腺癌、结肠癌、前列腺癌和胰腺癌的总和。败血症发生在50个住院病人中的1个，是重症监护病房的主要死亡原因。脓毒症的病例在过去十年中翻了一番，预计还会增加。脓毒症的主要原因之一是脂多糖(LPS)，它是革兰氏阴性细菌细胞壁的主要成分，也是天然免疫系统促炎反应的原型诱导剂。促炎反应的失调可导致脓毒症。最近，哺乳动物对内毒素的受体被发现是Toll样受体(TLR)-4，它的激活激活了一个信号转导通路，启动了促炎反应。我们之前已经展示了一种称为MAL的适配器蛋白在TLR-4激活时介导信号转导通路中的关键作用。MAL与一种名为TRAF6的关键信号转导介质的相互作用已被证明诱导促炎反应的激活。此外，已发现MAL发生了降解，这可能表明了一种调节促炎途径持续激活的方法。这项研究计划将研究MAL在TLR激活的巨噬细胞中的信号转导中的作用，巨噬细胞是先天免疫系统对微生物感染的关键反应细胞。更好地了解这些过程将有助于开发治疗方法，以减轻微生物引起的炎症的后果，包括慢性炎症性疾病和脓毒症。

Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune system. Dysregulation of the pro-inflammatory response can lead to sepsis. Recently, the mammalian receptor for LPS was found to be Toll-like receptor (TLR)-4, the activation of which activates a signal transduction pathway that initiates the pro-inflammatory response. We have previously shown a key role for an adapter protein called Mal in mediating signal transduction pathways upon activation of TLR-4. Interaction of Mal with a key signal transduction mediator called TRAF6 has been shown to induce the activation of the pro-inflammatory response. Furthermore, Mal has been found to undergo degradation which may indicate a means of regulating the continued activation of the pro-inflammatory pathway. This research program will investigate the role of Mal in mediating signal transduction in TLR activated macrophages, key responsive cells of the innate immune system to microbial infection. A greater understanding of these processes will assist in the development of therapeutics to alleviate the consequences of microbial-induced inflammation, including chronic inflammatory diseases and sepsis.