Decoding innate immune signaling in normal and myelodysplastic hematopoiesis

摘要 骨髓增生异常综合征(MDS)是一种异种且鲜为人知的造血干细胞 (HSC)在60岁以上的人中常见的衰竭综合征。随着预期寿命的增加， MDS的发病率继续上升，并将很快成为老年人最常见的血液系统疾病。 由于对MDS患者潜在的疾病认识不足，目前尚无有效的治疗方法 病理生物学和缺乏忠实的小鼠模型。我们的研究计划致力于填补这些空白， 然后利用由此产生的知识和工具来开发有效的药物疗法。已经，我们 已经在MDS HSCs中发现了遗传驱动的先天免疫通路的异常激活。我们 还发现了正常HSCs中先天免疫通路的一个关键功能，它具有 对慢性免疫相关疾病、心血管疾病和造血的影响。我们 假设调节失调的先天免疫信号是启动和 MDS的发展，是一种可行的治疗靶点。在这里，我们建议通过以下方式来检验这一假设 开展以下免费三部分研究计划：(1)解剖遗传学和细胞学 MDS HSCs的基础，强调细胞内在和细胞外源性免疫-炎症 各种因素。(2)鉴定和鉴定驱动HSCs MDS表型的新的信号通路。(3) 开发治疗MDS的新治疗策略。我们的研究计划的结果将是 推进我们关于MDS的启动、进展和治疗的范式转换模型。

Abstract Myelodysplastic Syndromes (MDS) are heterogenous and poorly understood hematopoietic stem cell (HSC) failure syndromes common in individuals >60 years of age. With increased life expectancies, the incidence of MDS continues to rise, and will soon be the most prevalent hematologic disorder in elderly. There are no effective treatments for MDS patients, due to an insufficient understanding of the underlying pathobiology and a lack of faithful mouse models. Our research program is focused on filling these gaps, and then leveraging the resulting knowledge and tools to develop effective drug therapies. Already, we have discovered genetically-driven aberrant activation of innate immune pathways in MDS HSCs. We have also identified a critical function of innate immune pathways in normal HSCs, which has implications for chronic immune-related disorders, cardiovascular diseases, and hematopoiesis. We hypothesize that dysregulated innate immune signaling is a major contributor to the initiation and development of MDS, and is a feasible therapeutic target. Herein, we propose to test this hypothesis by carrying out the following complimentary 3-part research program: (1) Dissect the genetic and cellular underpinnings of MDS HSCs, with an emphasis on cell-intrinsic and cell-extrinsic immune-inflammatory factors. (2) Identify and characterize novel signaling pathways driving MDS phenotype in HSCs. (3) Develop novel therapeutic strategies for the treatment of MDS. The results of our research program will advance our paradigm-shifting model of the initiation, progression, and treatment of MDS.