Decoding innate immune signaling in normal and myelodysplastic hematopoiesis

解码正常和骨髓增生异常造血中的先天免疫信号

• 批准号: 10571337
• 负责人: Daniel Starczynowski
• 金额: $ 111.3万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2029-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571337
• 关键词: Acute leukemia; Age Years; Automobile Driving; Basic Science; Blood Cells; Bone Marrow; Cardiovascular Diseases; Cells; Chronic; Collection; Development; Disease; Dysmyelopoietic Syndromes; Elderly; Failure; Genetic; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Hereditary Disease; Immune; Immune signaling; Incidence; Individual; Inflammation; Inflammatory; Knowledge; Life Expectancy; Modality; Modeling; Molecular; Pathogenesis; Patients; Pharmacotherapy; Phenotype; Research; Signal Pathway; Syndrome; Testing; effective therapy; innate immune function; innate immune pathways; knowledge of results; mouse model; new therapeutic target; novel; novel therapeutic intervention; programs; therapeutic target; tool; treatment strategy

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.

摘要 骨髓增生异常综合征（MDS）是一种异质性造血干细胞， (HSC)在>60岁的个体中常见的失败综合征。随着预期寿命的增加， MDS的发病率持续上升，并将很快成为老年人中最普遍的血液病。 由于对MDS患者的基础疾病认识不足， 病理生物学和缺乏可靠的小鼠模型。我们的研究计划专注于填补这些空白， 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 已经发现了MDS HSC中先天免疫途径的遗传驱动的异常激活。我们 还确定了正常HSC中先天免疫途径的关键功能， 对慢性免疫相关疾病、心血管疾病和造血的影响。我们 假设先天性免疫信号传导失调是引发免疫缺陷的主要因素， MDS的发展，并且是可行的治疗靶点。在此，我们建议通过以下方式来检验这一假设： 进行以下三部分的研究计划：（1）解剖遗传和细胞 MDS HSC的基础，重点是细胞内源性和细胞外源性免疫炎症 因素(2)鉴定和表征HSC中驱动MDS表型的新型信号通路。（三） 开发治疗MDS的新治疗策略。我们的研究计划的结果将 推进我们的MDS的启动，进展和治疗的范式转变模型。