Targeting gasdermin D to treat myelodysplastic syndromes

以gasdermin D 为靶点治疗骨髓增生异常综合征

• 批准号: 10718497
• 负责人: Peng Ji
• 金额: $ 53.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718497
• 关键词: Age; Aging; Biological Assay; Bone Development; Bone Marrow; Bone Marrow Cells; Bone remodeling; CASP1 gene; CD34 gene; Cells; Cues; Data; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Family; Fc Receptor; Genes; Genetic; Hematopoietic; Hematopoietic stem cells; IL-6 inhibitor; Immune signaling; Immunotherapy; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin 6 Receptor; Interleukin-1; Interleukin-6; Knock-out; Knockout Mice; Mediating; Medical; Modeling; Mus; NF-kappa B; Pathogenesis; Pathway interactions; Patients; Permeability; Phenocopy; Phenotype; Population; Process; Proliferating; Proto-Oncogene Protein c-kit; Reporter; Role; Source; Stromal Cells; System; Testing; Therapeutic; Transgenic Mice; Transplantation; Up-Regulation; Wild Type Mouse; Xenograft procedure; age related; cytokine; experimental study; gain of function; high risk; in vivo; inhibitor; leukemia; mouse model; mutational status; novel; prevent; single-cell RNA sequencing; transplant model

Summary Bone marrow inflammation induced by the dysregulated innate immune system and inflammasome activation is increasingly indicated to be critical in the pathogenesis and progression of myelodysplastic syndromes (MDS). Despite the significant progress in this field in the past few years, one of the key unresolved questions is: what are the major regulators that mediate the development of bone marrow inflammation. Resolving this question will be critical for the development of novel immunotherapies to treat MDS and prevent its progression, which remains to be a critical unmet medical need. Using a mouse model of double knockout (DKO) of Diap1 and miR146a, both are involved in the innate immune signaling and significantly downregulated in patients with MDS, we revealed that the old DKO mice developed MDS due to the upregulation of pro-inflammatory cytokines in the bone marrow. One of the unique features of the DKO model is that these mice are phenotypically normal at younger age but develop MDS that eventually progress to leukemia with aging, which closely phenocopies the development and progression of MDS in patients. More recently, we showed that genetic depletion of IL-6 in the DKO mice significantly delayed MDS progression. However, IL-6 is one of the highly upregulated cytokines in DKO mice and MDS patients. Loss of IL-6 failed to revert the inflammatory bone marrow microenvironment and many MDS phenotypes in the DKO model. It is essential to reveal the common upstream regulator(s) that mediate the release of inflammatory cytokines. In this respect, IL-6 is a well-known downstream target of IL-1, which is released by inflammation induced pyroptotic cells. Pyroptosis is activated upon inflammasome assembly including NLRP3, which is a downstream target of NF-b and upregulated by the activation of the innate immune signaling. Activation of NLRP3 is a hall mark of MDS independent of mutation status. Upregulated and activated NLRP3 inflammasome activates caspase 1, which in turn cleaves gasdermin D. The cleaved gasdermin D results in increased cell permeability, pyroptosis, and the release of cytokines including IL-1 family. Given its central role in pyroptosis, gasdermin D could also be involved in the pathogenesis and progression of MDS. We therefore crossed DKO mice with gasdermin D knockout mice. Indeed, loss of gasdermin D markedly reverted MDS phenotypes in the DKO mice. Gasdermin D is also highly upregulated in patients with MDS. Our preliminary studies indicate that gasdermin D also mediates inflammation in bone marrow stromal cells. Based on these data, we hypothesize that gasdermin D mediated inflammatory cues and dysregulation of innate immune signaling in hematopoietic cells and bone marrow stromal cells are pivotal in facilitating MDS development and progression. To test this hypothesis, we will perform experiments in the following three aims. In aim 1, we will investigate the hematopoietic cell intrinsic mechanisms of gasdermin D in MDS development and progression. In aim 2, the role of gasdermin D in mediating the inflammatory bone marrow microenvironment will be analyzed. Aim 3 will focus on the translational respect through targeting gasdermin D to treat MDS. Successful completion of this project will have an important impact in understanding the pathogenesis of aging associated bone marrow inflammation in MDS and developing novel immunotherapies to treat MDS.

概括 骨髓炎症是由失调的先天免疫系统和炎性体激活引起的 越来越多地表明对骨髓增生综合征（MDS）的病原体和进展至关重要。 尽管过去几年中有重要的计划，但未解决的关键问题之一是：什么 是介导骨髓炎症发育的主要制定者。 将批评用于治疗MD和PROGRATION的新型免疫疗法的发展，这将是 使用双重敲除（DKO）的鼠标，仍然是至关重要的医疗需求 MiR146a，均参与先天免疫信号传导，并在MDS患者中显着下调 我们透露，旧的DKO小鼠由于促炎细胞因子的上调而形成了MD 骨髓。 年轻但发展MD，最终随着衰老的衰老而发展为白血病 最近，MD的发展和进展。 DKO小鼠显着延迟了MDS程序的进展。 DKO小鼠和MDS患者的IL-6损失未能恢复炎症性骨髓环境 DKO模型中的许多MDS表型。 介导炎症性细胞因子的释放。 通过炎症诱导的凋亡细胞释放。 包含NLRP3，它是NF-B的下游靶标，并通过先天免疫的激活而上调 信号传导 NLRP3炎性体激活caspase 1，从而裂解果气D。裂解的煤气蛋白D结果 细胞渗透性，凋亡和包括IL-1家族在内的细胞因子的释放增加。 在凋亡中，毒气蛋白D也可能参与MDS的发病机理和进展 与Gasdermin D淘汰小鼠越过DKO小鼠。 DKO小鼠的表型也很高 研究表明，基于这些的气体也会介导骨髓细胞的炎症 数据，我们假设Gasdermin D介导的炎症提示和先天免疫的失调 造血细胞和骨髓基质细胞中的信号传导在促进MDS发展和 进展。为了检验这一假设，我们将在AIM 1中执行皇帝。 研究Gasdermin DN MDS开发和程序的造血细胞内在机制。 在AIM 2中，将分析Gasdermin D在介导炎症性骨髓微环境中的作用。 AIM 3将通过靶向速度D治疗MDS来重点进行翻译 该项目将对理解衰老骨髓的发病机理产生重要的影响力 MDS的炎症并开发出新颖的免疫疗法以信任MD。