Signaling properties of driver mutations in clonal hematopoiesis of indeterminate potential (CHIP) as targets for diagnostics and therapeutic intervention

不确定潜力克隆造血 (CHIP) 驱动突变的信号传导特性作为诊断和治疗干预的目标

• 批准号: 508481183
• 负责人: Professor Dr. Carsten Müller-Tidow
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508481183?language=en
• 关键词: Signaling; properties; driver; mutations; clonal

Somatic mutations in hematopoietic stem cells which induce clonal expansion are commonly acquired during human aging. Clonal hematopoiesis of indeterminate potential (CHIP) constitutes an important risk factor for the development of hematological malignancies and cardiovascular disease and is associated with an increased all-cause mortality. A growing body of evidence suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities such as inflammation from previous infections, pre-existing comorbidities or low-grade inflammation occurring with aging (inflammaging). CHIP-specific molecular features might be important targets for diagnostics and development of specific therapies. In this project we aim to identify CHIP associated signaling pathways and surface marker expression patterns with advanced multi-omics single cell analysis tools. In preliminary work for this proposal we analyzed CHIP mutations in mobilized stem cell products from more than 600 patients undergoing stem cell leukapheresis. Also, we established a specific bioinformatics tool set for the analyses in this project. Multi-omics single cell analyses will be used to identify deregulated signaling pathways and surface marker patterns (CITE-Seq) across diverse CHIP mutations and cell types. Subsequently, we will overexpress and knockout CHIP-associated expression patterns/signaling pathways in CD34+ hematopoeitic stem cells (HSC) from cord blood and analyse in vitro and in vivo whether modification of signaling/inflammatory genes phenocopies candidate driver mutations. For the top-regulatory pathways/ targets for which specific inhibitors are available we will analyze in vitro- drug responses and will perform in vivo xenograft transplantation studies to evaluate the potential of the respective drugs to preferentially eradicate CHIP clones. Taken together, this project will reveal pathways/regulatory genes which might be used for diagnostics and potentially for therapeutic applications to suppress CHIP clones.

造血干细胞中诱导克隆膨胀的体细胞突变通常在人类衰老期间获得。不确定潜力（CHIP）的克隆造血作用是血液恶性肿瘤和心血管疾病发展的重要危险因素，并且与全因死亡率增加有关。越来越多的证据表明，发炎失调会导致克隆扩张和相关的合并症，例如先前感染，预先存在的合并症或衰老（炎症）发生的低度炎症。芯片特异性的分子特征可能是诊断和开发特定疗法的重要目标。 在此项目中，我们旨在通过高级多摩管单细胞分析工具来确定芯片相关的信号通路和表面标记表达模式。在该提案的初步工作中，我们分析了600多名正在接受干细胞白细胞手术的患者动员干细胞产物中的CHIP突变。此外，我们还建立了一个特定的生物信息学工具，用于该项目的分析。 多态单细胞分析将用于识别跨不同芯片突变和细胞类型的失调信号通路和表面标记模式（Cite-Seq）。随后，我们将过表达和敲除芯片相关的表达模式/信号传导途径/信号途径中的CD34+造血干细胞（HSC）中的脐带血和体外分析以及体内分析信号传导/炎症基因表苯甲酸表疗法候选驱动器突变是否修饰。对于可用特定抑制剂的最高调节途径/靶标，我们将分析体外药物反应，并将进行体内异种移植移植研究，以评估各自药物优先消除芯片克隆的潜力。综上所述，该项目将揭示可用于诊断的途径/调节基因，并可能用于抑制芯片克隆的治疗应用。