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

研究含有 ZU5 结构域的蛋白质作为 caspase 激活放大器的功能

基本信息

批准号：
10621402
负责人：
Cornelius Taabazuing
金额：
$ 24.9万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621402
关键词：
Advisory Committees Amplifiers Apoptosis Autoimmune Diseases Autoimmunity CASP1 gene CASP2 gene Caspase Cell Death Cessation of life Consensus DNA DNA Damage Data Dipeptidyl Peptidases Disease Feedback Flagellin Genotoxic Stress Goals Immune Immune system Immunomodulators Immunotherapeutic agent Inflammasome Inflammatory Innate Immune Response Innate Immune System Interleukin-1 Interleukin-18 Knowledge Lead Link Malignant Neoplasms Mediating Mentors Modeling Molecular Multiprotein Complexes N-terminal Outcomes Research Pathogenicity Pattern recognition receptor Peptide Hydrolases Phase Play Process Proteins Proteomics Publishing RNA Regulation Research Role Series Serine Protease Signal Transduction Stimulus Stress Structure Testing Therapeutic Training Tumor Suppressor Proteins UV Radiation Exposure Ubiquitination VDAC1 gene Viral Work adaptive immune response base cancer immunotherapy chemotherapy cytokine fighting functional genomics human disease immune activation immunoregulation improved inhibitor insight microbial multicatalytic endopeptidase complex novel pathogen recruit response sensor skills small molecule inhibitor therapeutic development therapeutic protein therapeutic target ubiquitin-protein ligase

项目摘要

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.

项目概要和摘要 Caspase-1是一种半胱氨酸蛋白酶，催化细胞因子的成熟，在先天性细胞因子的成熟过程中发挥着关键作用。以及对致病刺激的适应性免疫反应。 caspase-1 的失调与多种疾病有关自身免疫性疾病和癌症。同样，caspase-2 是一种半胱氨酸蛋白酶，对于调节细胞对导致 DNA 损伤的压力（例如化疗）的反应。 caspase-1 和 caspase- 2 由结构相似的传感器蛋白激活，这些蛋白感知细胞内的扰动并安装适当的反应，但传感器如何被激活然后依次激活的分子机制它们各自的蛋白酶尚不清楚。一系列种系编码的模式识别受体感知病原体的保守特征，并组装成称为炎性体的多蛋白复合物，招募并激活 caspase-1。 caspase-1 激活的共识模型是炎症小体首先被激活，然后它们依次激活 caspase-1。我们的初步数据表明 caspase-1 在炎症小体激活，进而激活更多的 caspase-1，但其分子机制是未知。 K99 指导阶段的目标是确定 caspase-1 在炎症小体中的作用激活。具体来说，我们将确定包含ZU5结构域的激活机制炎症小体、CARD8 和 NLRP1。在独立R00阶段，我们将应用来自指导阶段以确定另一个包含 ZU5 结构域的传感器的激活机制激活 caspase-2 以响应基因毒性应激 (PIDD)。我们的中心假设是 ZU5 域- 含有传感器蛋白的激活方式类似，它们激活的蛋白酶参与传感器激活，进而激活更多的蛋白酶。为了实现这些目标，我精心组合了一个高度互补的咨询团队，拥有指导我的道路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焦亡和细胞凋亡的认识监管并可能促进多种人类疾病的治疗开发工作。