Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis

DPP8/9 抑制剂诱导细胞焦亡机制的表征

基本信息

批准号：
10091387
负责人：
Daniel Bachovchin
金额：
$ 44.9万
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：
2018
资助国家：
美国
起止时间：
2018-02-23 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091387
关键词：
Alleles Apoptosis Autoimmune Diseases Biochemical Boronic Acids C-terminal CASP1 gene CRISPR screen Cancer Model Caspase Cell Death Cell Line Chimeric Proteins Cleaved cell Clinic Co-Immunoprecipitations Cytosol Data Development Dipeptides Genetic Goals Human Immune Immune system Immunotherapeutic agent Immunotherapy Inbred Strains Mice Inflammation Innate Immune System Knock-out Laboratories Lytic Malignant Neoplasms Mediating Molecular Molecular Chaperones Mus N-terminal Natural Immunity New Agents Pathogenicity Pathway interactions Patients Peptide Hydrolases Peptides Pharmacology Population Proteasome Inhibitor Proteins Public Health Rat Strains Regulation Research Research Project Grants Resistance Role Serine Serine Protease Signal Pathway Stimulus Testing Therapeutic Toxoplasma gondii Toxoplasmosis Work anthrax lethal factor base cancer cell cancer immunotherapy cancer therapy cell type cytotoxic experimental study genome-wide improved inhibitor/antagonist innovation insight macrophage monocyte mouse model novel novel strategies pathogen peptide I polypeptide response sensor small molecule trafficking tumor

Alleles Apoptosis Autoimmune Diseases Biochemical Boronic Acids C-terminal CASP1 gene CRISPR screen Cancer Model Caspase Cell Death Cell Line Chimeric Proteins Cleaved cell Clinic Co-Immunoprecipitations Cytosol Data Development Dipeptides Genetic Goals Human Immune Immune system Immunotherapeutic agent Immunotherapy Inbred Strains Mice Inflammation Innate Immune System Knock-out Laboratories Lytic Malignant Neoplasms Mediating Molecular Molecular Chaperones Mus N-terminal Natural Immunity New Agents Pathogenicity Pathway interactions Patients Peptide Hydrolases Peptides Pharmacology Population Proteasome Inhibitor Proteins Public Health Rat Strains Regulation Research Research Project Grants Resistance Role Serine Serine Protease Signal Pathway Stimulus Testing Therapeutic Toxoplasma gondii Toxoplasmosis Work anthrax lethal factor base cancer cell cancer immunotherapy cancer therapy cell type cytotoxic experimental study genome-wide improved inhibitor/antagonist innovation insight macrophage monocyte mouse model novel novel strategies pathogen peptide I polypeptide response sensor small molecule trafficking tumor

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项目摘要

PROJECT SUMMARY Cancer immunotherapy – where the immune system is unleashed to destroy cancer cells – is a revolutionary new approach for combating cancer. However, even though immunotherapy has achieved unprecedented efficacies in the clinic, many cancers are not yet amenable to immune therapy, and even for those that are, a majority of patients fail to respond. New agents with improved or complementary mechanisms of action are therefore needed. One intriguing, yet poorly understood potential cancer immunotherapy agent is the small molecule Val-boroPro. Val-boroPro induces immune-mediated tumor regressions in multiple mouse models of cancer by inducing pyroptosis, a lytic form of programmed cell death, in monocytes and macrophages. Notably, Val-boroPro was the first small molecule discovered that induces pyroptosis. It is now established that inhibition of the cytosolic serine peptidases DPP8 and DPP9 (DPP8/9) by VbP activates the pro-protein form of caspase-1 to mediate cell death, but how DPP8/9 inhibition leads to the activation of caspase-1 remains entirely unknown. The long-term goal of this project is to successfully harness this pathway for cancer immunotherapy. The objective of this proposal is to determine how the inhibition of DPP8/9 induces pyroptosis in monocytes and macrophages. The central hypothesis is that DPP8/9 cleave and inactivate one or more peptides, which, if not cleaved, activates the innate immune sensor protein Nlrp1. Activated Nlrp1 then activates pro-caspase-1, triggering pyroptosis. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory and described in the application. This hypothesis will be tested by pursuing three specific aims: 1) Determine strain, species, and cell type sensitivity to DPP8/9 inhibitors, as Nlrp1 is highly polymorphic and varies considerably across strains and species; 2) determine the molecular mechanism of Nlrp1 activation by DPP8/9 inhibitors; and 3) determine the function of a specific co- chaperone required for DPP8/9 inhibitor-induced pyroptosis, which we hypothesize is responsible for the stability, folding, or trafficking of a key pyroptosis factor (e.g., Nlrp1 or the DPP8/9 substrate). Successful completion of this proposal will uncover new principles and mechanisms regulating the innate immune system, providing insights into pathogen recognition, autoimmune disorders, and inflammation. Moreover, this work has extraordinary potential to identify new targets and strategies that could form the bases of novel cancer immunotherapies.

项目摘要癌症免疫疗法 - 免疫系统被释放以破坏癌细胞 - 是革命性的与癌症作斗争的新方法。但是，即使免疫疗法取得了前所未有的诊所中的efucica是许多癌症尚不适合免疫治疗的癌症，甚至对于那些是大多数患者无法反应。具有改进或完整作用机理的新代理是因此需要。一个有趣但又不了解潜在的癌症免疫疗法的是小的分子瓣孔。 Val-Boropro在多种小鼠模型中诱导免疫介导的肿瘤回归单核细胞和巨噬细胞中诱导的凋亡（一种裂解形式的裂解形式）。值得注意的是，Val-Boropro是第一个小分子，发现影响凋亡。现在已建立通过VBP抑制胞质丝氨酸PETIDass DPP8和DPP9（DPP8/9） caspase-1的形式介导细胞死亡，但DPP8/9抑制如何导致caspase-1的激活仍然是完全未知的。该项目的长期目标是成功利用这一途径癌症免疫疗法。该提案的目的是确定DPP8/9的抑制如何引起单核细胞和巨噬细胞中的凋亡。中心假设是DPP8/9清除并灭活一个或更多的肽，如果不切割，则激活先天免疫蛋白NLRP1。激活的NLRP1 然后激活pro-Caspase-1，触发凋亡。该假设是根据在应用程序的实验室中产生的初步数据并在应用程序中进行了描述。这个假设将会通过追求三个特定目的来测试：1）确定对DPP8/9的菌株，物种和细胞类型的敏感性抑制剂，因为NLRP1是高度多态的，并且各种菌株和物种都一致。 2）确定 DPP8/9抑制剂激活NLRP1的分子机制； 3）确定特定共同的功能 DPP8/9抑制剂诱导的凋亡所需的伴侣，我们认为这是造成的关键的凋亡因子的稳定性，折叠或运输（例如NLRP1或DPP8/9底物）。成功的该提案的完成将揭示新的原则和机制，以应对先天免疫系统，提供有关病原体识别，自身免疫性疾病和炎症的见解。而且，这项工作具有非凡的潜力来确定可能构成新颖基础的新目标和策略癌症免疫疗法。