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 由先天免疫系统失调和炎症小体激活引起的骨髓炎症是 越来越多的证据表明其在骨髓增生异常综合征（MDS）的发病机制和进展中至关重要。 尽管过去几年该领域取得了重大进展，但尚未解决的关键问题之一是： 是介导骨髓炎症发展的主要调节因子。解决这个问题 对于开发治疗 MDS 并预防其进展的新型免疫疗法至关重要 仍然是一个未满足的关键医疗需求。使用 Diap1 和双敲除 (DKO) 小鼠模型 miR146a 均参与先天免疫信号传导，并在 MDS 患者中显着下调， 我们发现，老年 DKO 小鼠由于体内促炎细胞因子的上调而患上 MDS。 骨髓。 DKO 模型的独特特征之一是这些小鼠在 年龄较轻，但会发展为 MDS，最终随着年龄的增长发展为白血病，其表型与 患者MDS的发生和进展。最近，我们发现 IL-6 的基因缺失 DKO 小鼠显着延缓了 MDS 的进展。然而，IL-6 是体内高度上调的细胞因子之一。 DKO 小鼠和 MDS 患者。 IL-6 的缺失未能恢复炎症性骨髓微环境，并且 DKO 模型中存在许多 MDS 表型。有必要揭示常见的上游调节器 介导炎症细胞因子的释放。在这方面，IL-6 是众所周知的 IL-1 下游靶标， 它是由炎症诱导的焦亡细胞释放的。细胞焦亡在炎症小体组装时被激活 包括 NLRP3，它是 NF-κB 的下游靶标，通过先天免疫的激活而上调 发信号。 NLRP3 的激活是 MDS 的一个标志，与突变状态无关。上调并激活 NLRP3 炎症小体激活 caspase 1，进而裂解gasdermin D。裂解后的gasdermin D 结果 细胞通透性增加、细胞焦亡以及包括 IL-1 家族在内的细胞因子的释放。鉴于其核心作用 在细胞焦亡中，gasdermin D 也可能参与 MDS 的发病机制和进展。我们因此 DKO 小鼠与 Gasdermin D 敲除小鼠杂交。事实上，gasdermin D 的缺失可显着恢复 MDS DKO 小鼠的表型。 Gasdermin D 在 MDS 患者中的表达也高度上调。我们的初步 研究表明，gasdermin D 还介导骨髓基质细胞的炎症。基于这些 根据数据，我们假设 Gasdermin D 介导炎症信号和先天免疫失调 造血细胞和骨髓基质细胞中的信号传导对于促进 MDS 的发展和发展至关重要 进展。为了检验这个假设，我们将在以下三个目标上进行实验。在目标 1 中，我们将 研究 Gasdermin D 在 MDS 发生和进展中的造血细胞内在机制。 在目标 2 中，将分析gasdermin D 在介导炎症骨髓微环境中的作用。 目标3将重点关注通过靶向gasdermin D来治疗MDS的转化方面。顺利完成 该项目将对理解衰老相关骨髓的发病机制产生重要影响 MDS 中的炎症并开发新的免疫疗法来治疗 MDS。