Coordination Funds

造血干细胞/祖细胞中髓性白血病相关基因的体细胞突变的获得与正常的衰老过程相吻合，导致突变的血细胞克隆的生长（克隆造血，CH）。CH在60岁以上的人群中非常普遍。我们和其他人在过去5年的深入研究表明，CH具有重要的病理生理意义。虽然CH与进展为血液系统恶性肿瘤的风险增加有关，但CH已成为动脉粥样硬化、冠心病、心力衰竭和主动脉瓣狭窄的一个意想不到的独立危险因素和驱动因素。最大的医学兴趣的主题需要一个跨学科的研究单位（称为HERZBLUT）跨越血液学和心血管医学的边界。我们拥有一支由这些领域的世界领先专家和新兴初级研究人员组成的强大团队，将强大的生命科学和医学研究经验与先进的技术和先进的研究方法相结合。基础和临床科学家密切互动，将知识从分子和细胞为基础的模型转移到临床前模型和临床应用，并使从特征明确的患者队列的主要材料反向翻译回实验室。对某些基因（DNMT3A, TET2, PPM1D, SRSF2, SF3B1），突变和ch相关疾病（心力衰竭，瓣膜狭窄，肺动脉高压，急性髓性白血病）的限制将在HERZBLUT内共享共同技术，模型和研究工具方面产生高度协同作用，并有助于建立一个广泛而统一的疾病机制。我们在此提出了一个全面和高度协同的工作计划，以遵循两个主要目标：a)针对CH的治疗应用的病理机制，b)在CH相关疾病的背景下询问CH的发生和进展。通过HERZBLUT，我们追求以下目标：(1)通过研究CH及其相关的心脏和血液疾病的分子和细胞病理机制，促进CH及其相关疾病领域的精确生物学。(2)开发新的个体化治疗机制，促进精准医疗。(3)促进初级科学家和临床医生进行基础和转化研究。(4)招募和提拔优秀的女科学家和临床医生。(5)通过申请专利和利用我们新获得的知识，促进诊断和治疗方法的发展。(6)采取一系列广泛的措施，为科学界和医学界以及广大公众开展公众宣传。HERZBLUT的精致组成，加上优秀而严格的研究计划，将确保我们在开发关键知识和翻译工具方面的努力，用于心脏和血液中CH和CH相关疾病的临床管理。

The acquisition of somatic mutations in hematopoietic stem/progenitor cells in myeloid-leukemia-related genes coincides with the normal aging process and leads to the outgrowth of mutated blood cell clones (clonal hematopoiesis, CH). CH is highly prevalent in individuals over the age of 60. Intensive research by us and others over the last 5 years have revealed that CH has major pathophysiological implications. While CH is associated with enhanced risk to progress into hematologic malignancies, CH has emerged as an unexpected, independent risk factor and driver of atherosclerosis, coronary heart disease, heart failure and aortic valve stenosis. The topic of utmost medical interest requires a transdisciplinary Research Unit (entitled HERZBLUT) crossing the boarders of hematology and cardiovascular medicine. We present a strong team of world-leading experts in these fields and emerging junior investigators to pair strong life science and medical research experience with sophisticated technologies and advanced research approaches. Basic and clinician scientists closely interact to transfer the knowledge from molecular and cell-based models to preclinical models and clinical application, and to enable the reverse translation of primary material from well characterized patient cohorts back to the lab. The restriction on certain genes (DNMT3A, TET2, PPM1D, SRSF2, SF3B1), mutations and CH-associated diseases (heart failure, valve stenosis, pulmonary hypertension, acute myeloid leukemia) will generate high synergisms in sharing common technologies, models, and research tools within HERZBLUT, and help to build a broad and unifying picture of overarching disease mechanisms. We propose here a comprehensive and highly synergistic work program to follow two major aims: a) to target the pathomechanisms of CH for therapeutic applications and b) to interrogate CH development and progression in the context of CH-associated diseases. With HERZBLUT, we pursue following objectives: (1) To promote precision biology in the field of CH and its associated diseases of the heart and the blood by studying the molecular and cellular pathomechanisms. (2) To exploit mechanistic findings for novel individualized therapies, promoting precision medicine. (3) To promote junior scientists and clinicians for basic and translational research. (4) To recruit and promote outstanding female scientists and clinicians. (5) To facilitate the development of diagnostic and therapeutic approaches by patenting and exploiting our newly gained knowledge. (6) To install a broad array of measures addressing public outreach for the scientific and medical community and for the general public. The exquisite composition of HERZBLUT, paired with an excellent and stringent research plan, will ensure our efforts in developing critical knowledge and in translating tools for clinical management of CH and CH-associated diseases in the heart and blood.