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：
10240450
负责人：
Cornelius Taabazuing
金额：
$ 10.68万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-17 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240450
关键词：
Advisory Committees Amplifiers Apoptosis Autoimmune Diseases Autoimmunity CASP1 gene CASP2 gene Caspase Cell Death Cessation of life Cleaved cell 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/antagonist 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.

项目摘要和摘要 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性中起关键作用和对致病性刺激的自适应免疫反应。 caspase-1的不正调与各种自身免疫性疾病和癌症。同样，caspase-2是半胱氨酸蛋白酶，对于调节很重要细胞对引起DNA损伤的应激的反应，例如化学疗法。 caspase-1和caspase- 2被结构相似的传感器蛋白激活，这些传感器蛋白会感知细胞内扰动和安装适当的响应，但是传感器如何激活的分子机制然后激活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病原体的理性保守特征，并将其组装成称为炎症的多蛋白质复合物，募集和激活caspase-1。 caspase-1激活的共识模型是炎症体是首先激活，然后它们又激活了caspase-1。我们的初步数据表明caspase-1在炎性体激活又激活了更多的caspase-1，但是，分子机制是未知。在K99指导阶段的目标是确定caspase-1在炎症中的作用激活。具体而言，我们将确定含Zu5域的激活机制炎症，Card8和NLRP1。在独立R00阶段，我们将应用指导阶段确定另一个含Zu5结构域传感器的激活机制激活caspase-2响应遗传毒性应激，PIDD。我们的中心假设是Zu5域 - 含有传感器蛋白的蛋白质以类似的方式激活，其中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，我已经仔细集会了一个高度互补的咨询团队，具有指导我通往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了解我们对凋亡和凋亡的理解调节，并有可能为各种人类疾病提高治疗性开发工作。