Investigating the function of ZU5 domain-containing proteins as amplifiers of caspase activation

项目总结和摘要 Caspase-1是一种半胱氨酸蛋白酶，可催化细胞因子的成熟，并在先天免疫中发挥关键作用。 和对病原刺激的适应性免疫反应。caspase-1的失调与多种 自身免疫性疾病和癌症。类似地，胱天蛋白酶-2是一种半胱氨酸蛋白酶，其对于调节 细胞对导致DNA损伤的应激反应，如化疗。caspase-1和caspase- 2被结构相似的传感蛋白激活，这些传感蛋白感知细胞内的扰动， 适当的反应，但如何传感器被激活，然后反过来激活的分子机制， 它们各自的蛋白酶还不太清楚。一系列种系编码的模式识别受体 感知病原体的保守特征，并组装成称为炎性小体的多蛋白复合物， 其募集并激活半胱天冬酶-1。半胱天冬酶-1激活的共识模型是，炎性小体 首先激活，然后它们依次激活半胱天冬酶-1。我们的初步数据表明，caspase-1在 炎性小体激活，进而激活更多的caspase-1，然而，分子机制是 未知K99指导阶段的目标是确定caspase-1在炎性小体中的作用， activation.具体来说，我们将确定含ZU 5结构域的 炎性小体、CARD 8和NLRP 1。在独立R 00阶段，我们将应用来自 指导阶段，以确定另一个包含ZU 5域的传感器的激活机制， 激活半胱天冬酶-2响应遗传毒性应激，PIDD。我们的中心假设是ZU 5结构域- 含有传感蛋白的蛋白酶以类似的方式被激活，其中它们激活的蛋白酶参与 传感器激活，这反过来又激活更多的蛋白酶。为了实现这些目标，我精心组织了 一个高度互补的咨询团队，具有指导我实现以下目标所需的科学和指导技能： 研究独立性。这项工作的完成将进一步加深我们对细胞凋亡和细胞凋亡的认识 监管，并有可能推进各种人类疾病的治疗开发工作。

PROJECT SUMMARY AND ABSTRACT Caspase-1 is a cysteine protease that catalyzes the maturation of cytokines and plays critical roles in the innate and adaptive immune response to pathogenic stimuli. Misregulation of caspase-1 is associated with various autoimmune diseases and cancer. Similarly, caspase-2 is a cysteine protease that is important for regulating the cellular response to stresses that cause DNA damage, such as chemotherapy. Both caspase-1 and caspase- 2 are activated by structurally similar sensor proteins that sense intracellular perturbations and mount appropriate responses, but the molecular mechanism of how the sensors are activated and then in turn activate their respective proteases, is not well understood. A series of germline-encoded pattern recognition receptors sense conserved features of pathogens, and assemble into multiprotein complexes called inflammasomes, which recruit and activate caspase-1. The consensus model for caspase-1 activation is that inflammasomes are first activated then they in turn activate caspase-1. Our preliminary data suggests that caspase-1 plays a role in inflammasome activation, which in turn activates more caspase-1, however, the molecular mechanism is unknown. The goal during the K99 mentored phase, is to determine the role caspase-1 plays in inflammasome activation. Specifically, we will determine the activation mechanism of the ZU5 domain-containing inflammasomes, CARD8 and NLRP1. During the independent R00 phase, we will then apply the training from the mentored phase to determine the activation mechanism of another ZU5 domain-containing sensor that activates caspase-2 in response to genotoxic stress, PIDD. Our central hypothesis is that the ZU5 domain- containing sensor proteins are activated in a similar manner, in which the proteases they activate participate in sensor activation, which in turn activates more protease. To accomplish these goals, I have carefully assembled a highly complementary advisory team with the scientific and mentoring skills needed to guide my path to research independence. The completion of this work will further our understanding of pyroptosis and apoptosis regulation and could potentially advance therapeutic development efforts for a variety of human diseases.