The role of ZAK in Shiga toxin/ricin-induced inflammation

描述(申请人提供)：炎症反应是许多感染的自然后果，可以是一种关键的保护性反应。然而，在某些情况下，炎症可能会对宿主造成毁灭性的影响。人类不慎中毒志贺毒素或蓖麻毒素的案例时有发生，影响严重，有时甚至致命，因此它们被认为是潜在的生物恐怖因子。这些毒素的一个作用是刺激宿主炎症，最终损害宿主。目前还没有针对醉酒引起的疾病的既定治疗方法。为了充分了解与这些蛋白质合成抑制剂相关的独特中毒综合征，有必要确定疾病发病机制的哪些方面是由于蛋白质合成抑制本身，以及哪些方面是由目前与这些毒素相关的新的免疫激活特性引起的。我们的总体目标是研究志贺毒素/蓖麻毒素激活的导致宿主破坏性炎症的关键宿主蛋白。这些宿主蛋白可能成为预防或治疗志贺毒素/蓖麻毒素相关疾病的潜在治疗靶点。我们是第一个发现MAP3Kinase(称为‘ZAK’)的小组，该酶与这些毒素启动的促炎信号级联反应有关。我们的总体假设是志贺毒素/蓖麻毒素诱导的ZAK激活通过引起宿主损伤性炎症而导致总体宿主发病率/死亡率，ZAK可能是一个潜在的治疗靶点。据我们所知，我们是唯一一个致力于通过靶向参与促炎信号级联反应的MAP3Kinase(S)来开发志贺毒素/蓖麻毒素引起的炎症的治疗方法的小组。在这项建议中，我们将创建一个ZAK基因定向缺失的小鼠株系，用于志贺毒素/蓖麻毒素攻击模型，在该模型中可以研究免疫介导的损伤机制。我们将启动研究，以确定Zak在基础或中毒条件下在细胞中的定位。我们将使用几种互补的方法识别潜在的ZAK相互作用分子，并评估ZAK与其结合伙伴之间的相互作用(S)。这些分子可能成为新的治疗靶点。 与公共卫生相关：人类不慎中毒志贺毒素或蓖麻毒素可能会导致严重的、有时是致命的影响。因此，他们被认为是潜在的生物恐怖分子。目前还没有针对这些病原体引起的疾病的具体治疗方法，因此了解这些毒素是如何损害宿主细胞的，对于了解如何预防因无意或故意接触而发生的疾病至关重要。

DESCRIPTION (provided by applicant): Inflammatory responses are natural consequences of many infections and can be a key protective response. However, in some cases, inflammation can cause devastating effects on the host. Cases of inadvertent intoxication of humans with either Shiga toxins or ricin occur, with serious and sometimes fatal effects, thus they are considered potential bioterror agents. One effect of these toxins is to stimulate host inflammation that ultimately damages the host. There are no established treatments for the diseases resulting from intoxication. To fully understand the unique intoxication syndromes associated with these protein synthesis inhibitors, it is essential to determine which aspects of disease pathogenesis are due to protein synthesis inhibition per se, and which aspects result from the novel immune activating properties now associated with these toxins. Our overall goal is to investigate critical host proteins activated by Shiga toxins/ricin that result in host-damaging inflammation. These host proteins would be potential therapeutic targets to prevent or treat Shiga toxin/ricin-associated diseases. We are the first group to identify a MAP3Kinase (called 'ZAK') that is associated with the proinflammatory signaling cascade initiated by these toxins. Our overall hypothesis is that Shiga toxin/ricin-induced ZAK activation contributes to overall host morbidity/mortality by causing host-damaging inflammation, and that ZAK may be a potential therapeutic target. To the best of our knowledge, we are the only group working on development of therapeutics for Shiga toxin/ricin-induced inflammation by targeting the MAP3Kinase(s) involved in the proinflammatory signaling cascade. In this proposal, we will create a murine line with a targeted deletion in ZAK, for use in Shiga toxin/ricin challenge models in which the mechanisms underlying immune-mediated damage can be studied. We will initiate studies to determine ZAK localization in cells under basal or intoxicated conditions. We will identify potential ZAK-interacting molecules using several complementary approaches, and evaluate the interaction(s) between ZAK and its binding partners. These molecules may be new therapeutic targets. PUBLIC HEALTH RELEVANCE: Inadvertent intoxication of humans with either Shiga toxins or ricin can cause serious and sometimes fatal effects. As a result, they are considered potential bioterror agents. There are no specific treatments for diseases caused these agents, so understanding how these toxins harm host cells is critical to understanding how to prevent illnesses that occur following inadvertent or intentional exposure.