Characterization of the Role of Bruton`s Tyrosine Kinase (BTK) for Myeloid Cell Function in Mouse and Man

布鲁顿酪氨酸激酶 (BTK) 对小鼠和人类骨髓细胞功能作用的表征

• 批准号: 207627402
• 负责人: Professorin Dr. Cornelia Brunner
• 金额: --
• 依托单位: Forschungsbereich Onkologie / Tumorimmunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/207627402?language=en
• 关键词: Characterization; Role; Bruton; Tyrosine; Kinase

Mutations within the gene coding for Bruton’s Tyrosine Kinase (BTK) cause X-linked agammaglobulinemia (XLA) in man, which is characterized by the almost complete absence of mature B cells within the circulation accompanied by the lack of immunoglobulins and therefore by a high susceptibility to recurrent bacterial infections. A recent study revealed that only 26% of 201 patients suffering from XLA were aged 21 years or older. However, BTK is expressed not exclusively in B cells but also in other hematopoietic cells including cells of the myeloid lineage but the impact of BTK to the function of XLA myeloid cells is discussed controversial. Recently, we have shown a profound maturation and functional defect of Btk-deficient neutrophilic granulocytes in mice. To get more insight into the role of BTK for the myeloid compartment we suggest here new attempts and approaches. Using in vivo experimental mouse models depending in a first line mainly on the action of myeloid cells, like the experimental autoimmune encephalomyelitis (EAE) or wound healing models, or human myeloid cells in which BTK expression or function will be down-modulated, and also “humanized mice” presenting human hematopoietic cells in which BTK expression will be knocked-down, we expect results that engross our knowledge about the role of Btk/BTK for myeloid cell development and function in mouse and man. Finally, these results may alter our understanding about the pathogenesis of XLA as well as therapy approaches for treatment of affected patients.

布鲁顿氏酪氨酸激酶 (BTK) 基因编码突变会导致人类 X 连锁无丙种球蛋白血症 (XLA)，其特征是循环中几乎完全缺乏成熟 B 细胞，同时缺乏免疫球蛋白，因此对反复细菌感染高度敏感。最近的一项研究显示，201 名 XLA 患者中，只有 26% 的年龄在 21 岁或以上。然而，BTK 不仅在 B 细胞中表达，还在包括骨髓谱系细胞在内的其他造血细胞中表达，但 BTK 对 XLA 骨髓细胞功能的影响存在争议。最近，我们发现 Btk 缺陷的小鼠中性粒细胞存在严重的成熟和功能缺陷。为了更深入地了解 BTK 对骨髓室的作用，我们在此建议新的尝试和方法。使用主要依赖于骨髓细胞作用的体内实验小鼠模型，如实验性自身免疫性脑脊髓炎（EAE）或伤口愈合模型，或其中BTK表达或功能将被下调的人骨髓细胞，以及呈现人类造血细胞的“人源化小鼠”，其中BTK表达将被敲低，我们期望结果能够吸收我们关于骨髓细胞作用的知识。 Btk/BTK 用于小鼠和人类骨髓细胞的发育和功能。最后，这些结果可能会改变我们对 XLA 发病机制以及受影响患者治疗方法的理解。