权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular mechanisms for bone marrow failure and clonal progression during the innate immune response in Fanconi Anemia

范可尼贫血先天免疫反应期间骨髓衰竭和克隆进展的分子机制

基本信息

批准号：
9895782
负责人：
Elizabeth Ann Eklund
金额：
$ 35.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895782
关键词：
ATR checkpoint Adjuvant Adverse effects Anemia Antigens Apoptosis Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Transplantation CD34 gene CSF3 gene Candida Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cells Cessation of life Childhood Chronic Clonal Expansion Complement Complication Congenital Disorders DNA DNA Damage DNA Repair DNA Repair Pathway DNA replication fork Disease Dysplasia Emergency Situation Erythroid Event Expression Profiling Fanconi&apos s Anemia Functional disorder Gene Expression Genes Genetic Models Genetic Transcription Genotoxic Stress Goals Granulopoiesis Hematopoiesis Hematopoietic Hereditary Disease Human Infection Inflammation Inherited Injections Innate Immune Response Interleukin-1 Interleukin-1 beta Interruption Lead Mediating Molecular Morbidity - disease rate Mus Mutagenesis Mutation Myelogenous Myeloid Leukemia NADPH Oxidase Pancytopenia Pathway interactions Patients Phagocytes Process Production Reactive Oxygen Species Recurrence Regulatory Pathway Resistance Role S Phase Signal Transduction Stimulus Stress Survivors TP53 gene Testing Therapeutic Wild Type Mouse adverse outcome aluminum sulfate crosslink cytokine density granulocyte granulocyte-monocyte progenitors hematopoietic stem cell expansion leukemia mortality mouse model novel pathogen preclinical study prevent progenitor repaired response screening small molecule inhibitor stem stem cells transcription factor

项目摘要

The Fanconi DNA repair pathway is required for rescue of stalled or collapsed replication forks. Fanconi Anemia (FA) is caused by inherited mutation of Fanconi genes. FA patients develop bone marrow failure (BMF) in childhood, with survivors frequently developing clonal progression. We identified a role for emergency (stress) granulopoiesis (EG) in BMF and clonal progression in FA. EG is an episodic process for granulocyte production in response to infectious challenge. During EG, S phase is shortened and FancC and F expression increase. Unlike wild type mice, Fancc-/- mice did not develop granulocytosis upon stimulation of EG. Repeated EG challenge in Fancc-/- mice induced either BMF, with apoptosis of HSC and progenitors, or clonal progression. Treatment of Fancc-/- mice with an IL1-R antagonist protected them from these adverse consequences. IL1β is an essential cytokine for EG; inducing myeloid lineage commitment, and G-CSF expression. During the S phase, Atr activates p53 and apoptosis of cells with unrepaired replication fork damage. In Fancc-/- mice, Tp53-haplo- insufficiency rescued granulocytosis during EG; delaying BMF but accelerating clonal progression. In Fancc-/- mice, increasing activity of Atr/p53 occurred with each unsuccessful EG episode; associated with BMF. In contrast, Atr/p53 activity decreased with consecutive, successful EG cycles in Fancc-/-Tp53+/- mice. We hypothesize unsuccessful PMN production in FA during EG prevents activation of unknown negative regulatory pathways; sustaining cell cycle checkpoint activity and HSC/GMP expansion signals. This induces BMF and accumulation of mutations that lead to clonal progression. We will pursue this through three aims: Aim 1: Define molecular triggers for termination of emergency granulopoiesis and the role of this process in BMF in FA. We will investigate contribution of PMN density to apoptosis and BMF during unsuccessful EG in Fancc-/- mice. The impact of PMN bone marrow density on known EG-related pathways will be determined in Wt vs Fancc-/- mice, and novel pathways identified in non-biased studies. Aim 2: Identify events associated with emergency granulopoiesis-induced clonal progression in FA. We will define events involved in clonal progression in Fancc-/- mice by studying leukemia suppressor pathways that mediate EG termination and by non-biased approaches. Results will be compared to gene expression profiles in CD34+ bone marrow cells from human Fanconi Anemia to identify potential translational targets. Aim 3: Investigate potential translational targets to delay BMF or clonal progression in FA. We will determine the impact of novel pathways that are activated during EG on BMF and/or clonal progression in murine genetic models. Relevant intermediates with small molecule inhibitors will be tested in pre-clinical studies. The goal of these studies is to define molecular mechanisms for BMF and/or clonal progression during recurrent, unsuccessful EG attempts in FA. This may suggest therapeutic approaches to decrease morbidity due to anemia and infection, or bridge patients to definitive treatments such as stem cell/bone marrow transplant.

Fanconi DNA修复途径是拯救停滞或崩溃的复制叉所必需的。范科尼贫血（Anemia，FA）是由Fanconi基因的遗传性突变引起的。FA患者发生骨髓衰竭（BMF）在儿童时期，幸存者经常发展克隆进展。我们确定了紧急情况（压力）的作用 BMF中的粒细胞生成（EG）和FA中的克隆进展。EG是粒细胞产生的一个阶段性过程以应对传染病挑战。在EG期间，S期缩短，FancC和F表达增加。与野生型小鼠不同，Fancc-/-小鼠在EG刺激后未发生粒细胞增多症。重复EG Fancc-/-小鼠的攻击诱导BMF，伴随HSC和祖细胞的凋亡，或克隆进展。用IL 1-R拮抗剂治疗Fancc-/-小鼠可以保护它们免受这些不良后果。IL 1 β是 EG的必需细胞因子;诱导髓系定型和G-CSF表达。在S阶段， Atr激活p53和未修复复制叉损伤细胞的凋亡。在Fancc-/-小鼠中，Tp 53-haplo- 在EG期间，功能不全挽救了粒细胞增多症;延迟BMF但加速克隆进展。在Fancc-/- 在小鼠中，Atr/p53的活性增加发生在每次不成功的EG发作中;与BMF相关。在相反，在Fancc-/-Tp 53 +/-小鼠中，Atr/p53活性随着连续成功的EG循环而降低。我们假设在EG过程中FA中不成功的PMN产生阻止了未知阴性细胞的激活，调节途径;维持细胞周期检查点活性和HSC/GMP扩增信号。这诱导 BMF和导致克隆进展的突变积累。我们将通过三个目标实现这一目标：目的1：确定终止紧急粒细胞生成的分子触发因子及其作用在FA中的BMF中处理。我们将研究PMN密度对细胞凋亡和BMF的贡献，在Fancc-/-小鼠中不成功的EG。PMN骨髓密度对已知的EG相关通路的影响将在Wt与Fancc-/-小鼠中测定，并在无偏倚研究中鉴定了新的途径。目的2：确定与FA中紧急粒细胞生成诱导的克隆进展相关的事件。我们将通过研究白血病抑制通路来确定Fancc-/-小鼠克隆进展中涉及的事件介导EG终止和非偏倚方法。结果将与基因表达进行比较在来自人范可尼贫血的CD 34+骨髓细胞中的表达谱，以鉴定潜在的翻译靶点。目的3：研究延迟FA中BMF或克隆进展的潜在翻译靶点。我们将确定EG期间激活的新途径对小鼠BMF和/或克隆进展的影响，基因模型将在临床前研究中检测含小分子抑制剂的相关中间体。这些研究的目的是确定BMF和/或克隆进展的分子机制，在FA中反复进行不成功的EG尝试。这可能表明治疗方法，以减少发病率，贫血和感染，或桥梁患者的明确治疗，如干细胞/骨髓移植。