Constrained Fetal Hematopoiesis and Clonal Restriction in Fanconi Anemia

范可尼贫血中胎儿造血受限和克隆限制

• 批准号: 10377337
• 负责人: Peter Kurre
• 金额: $ 56.44万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377337
• 关键词: Activity Cycles; Adult; Affect; Age; Aldehydes; Alleles; Automobile Driving; Base Pairing; Birth; Bone Marrow; Bone marrow failure; Cell Compartmentation; Cell Count; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Kinetics; Cells; Cellular Stress; Clonality; Code; Complement; DNA Interstrand Cross-Link Repair; DNA Repair; DNA Repair Disorder; Data; Defect; Development; Environment; FANCD2 protein; Failure; Fanconi anemia protein; Fanconi' s Anemia; Fetal Liver; Frequencies; Gene Expression; Genes; Genetic Recombination; Genome Stability; Genomic Instability; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Hereditary Disease; Heritability; Inflammation; Inherited; Knockout Mice; Lead; Life; Measures; Modeling; Morbidity - disease rate; Mus; Mutation; Nuclear Translocation; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Physiological; Play; Positioning Attribute; Production; Reporting; Reserve Stem Cell; Resolution; Risk; Risk Factors; Role; S phase; School-Age Population; Shapes; Signal Pathway; Signal Transduction; TP53 gene; Testing; Thrombopoietin; Transforming Growth Factor beta; base; biological adaptation to stress; bone loss; cancer predisposition; cell type; cytopenia; exhaustion; experience; fetal; fetal blood; genome integrity; genome-wide; hematopoietic stem cell expansion; hematopoietic stem cell niche; hematopoietic stem cell self-renewal; hematopoietic transplantation; improved; in utero; inhibitor; insight; leukemia; loss of function; mortality; mouse model; novel; novel therapeutics; postnatal; pressure; programs; replication stress; response; restoration; self-renewal; single cell analysis; stem cells; whole genome

Summary This proposal explores a new model of Fanconi Anemia (FA) pathogenesis based on our findings that FA proteins protect hematopoietic stem cells (HSCs) from replication stress during the rapid developmental expansion in the fetal liver (FL). FA is a recessively inherited DNA repair disorder with cancer predisposition and near uniform bone marrow (BM) failure. While most FA patients experience symptomatic failure in early school age, BM hematopoietic stem cell (HSC) numbers are already compromised much earlier in life. We recently reported that the physiologic onset of HSC deficits in FA knockout mice occurs in utero. We now show that deficits in FA first emerge in the FL, caused by replication stress-associated Atr/Chk1 checkpoint engagement in immunophenotypically defined HSC. Because the HSC pool is typically complete at birth, these constraints constitute not only a previously unrecognized bottleneck for HSC pool formation in FA, but also pose a principal risk factor for rapid postnatal HSC exhaustion. To understand the exaggerated developmental vulnerability in the FA FL we have conducted additional preliminary studies of the FL microenvironment that implicate a subset of supportive cells forming the HSC niche. Altogether, we hypothesize that the physiological role of FA proteins is to safeguard in HSC pool clonality and genome integrity under conditions of replication stress. These observations lead us to test the long-term impact of fetal deficits in FA on HSC self-renewal and hematopoietic reserve. Specific Aim 1 ïDetermine absolute HSC pool size and clonal diversity as driving risk factors for HSC exhaustion in FA Specific Aim 2 ïDissect the long-term impact of checkpoint activation on genome stability and function in fetal FA HSC Specific Aim 3 ïIdentify the FL specific niche abnormalities that contribute to hematopoietic deficits in FA, and reveal the key signaling pathways that functionally limit HSC expansion Altogether, this project advances a new paradigm, whereby FA proteins enable developmental expansion and self-renewal divisions critical to clonal diversity and genome stability in the HSC pool. This positions developmental deficits in FA patients as a driving risk factor for HSC exhaustion and a critical cause for morbidity and mortality. Results will provide insight for the development of safe and effective new therapies that mitigate loss of hematopoietic function in FA.

概括 该提案探讨了基于我们的发现，探索了一种新的范科尼贫血（FA）发病机理的模型 蛋白质保护造血干细胞（HSC）免受快速发育过程中的复制应力 胎儿肝脏（FL）的膨胀。 FA是一种遗传遗传的DNA修复障碍，癌症易感性 和接近均匀的骨髓（BM）衰竭。虽然大多数FA患者早期都有症状失败 BM造血干细胞（HSC）数量已经在生活中遭受的损害已经很早了。我们 最近报道，HSC的生理开始定义在FA敲除小鼠中发生在子宫内。我们现在 显示在FA中定义在FL中定义的，这是由复制应力相关的ATR/CHK1检查点引起的 参与免疫表型定义的HSC。因为HSC池通常在出生时完成 这些约束不仅构成了FA中HSC池形成的先前未识别的瓶颈，而且还构成 还为快速产后HSC耗尽的主要风险因素带来了主要风险因素。理解夸张的 我们已经对FL进行了其他初步研究 微环境意味着形成HSC生态位的支持细胞的子集。总共，我们 假设FA蛋白的身体作用是保护HSC池克隆性和基因组 在复制应力条件下的完整性。这些观察结果使我们测试了 胎儿在​​HSC自我更新和造血储备中定义FA。 特定目标1 - 确定的绝对HSC池大小和克隆多样性作为驱动风险因素 FA中的HSC疲惫 具体目的2降低了检查点激活对基因组稳定性和的长期影响 胎儿FA HSC的功能 特定目的3识别有助于造血缺陷的FL特异性小众异常 在FA中，并揭示功能限制HSC扩展的关键信号通路 总之，该项目将推进一个新的范式，FA蛋白可以扩展发展 以及HSC库中克隆多样性和基因组稳定性至关重要的自我更新分裂。这个位置 发育性将FA患者定义为HSC耗竭的驱动风险因素，也是至关重要的原因 发病率和死亡率。结果将为开发安全有效的新疗法提供见解 减轻FA中造血功能的丧失。