Chromatin State Alterations in Fanconi Anemia Hematologic Disease and Bone Marrow Failure

范可尼贫血血液疾病和骨髓衰竭中的染色质状态改变

• 批准号: 10735366
• 负责人: Niall George Howlett
• 金额: $ 8.4万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10735366
• 关键词: ATAC-seq; Applications Grants; Award; Binding; Biochemistry; Biological Assay; Bone marrow failure; Cells; Chromatin; Chromosomal Instability; Chromosomal Stability; Complement; Congenital Abnormality; DNA Damage; DNA Repair; DNA Repair Gene; Data; Disease; Doctor of Philosophy; Enzymes; Epigenetic Process; Etiology; Exposure to; FANCD2 protein; Family; Fanconi Anemia Complementation Group A Protein; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; General Population; Genes; Genetic Diseases; Genetic Transcription; Goals; Hematological Disease; Hematopoietic Stem Cell Transplantation; Histones; Life Expectancy; Link; Methyltransferase; Molecular; Molecular Chaperones; Monoubiquitination; Mutation; Nucleosomes; Parents; Pathogenesis; Patients; Premature Mortality; Prognosis; Proteins; Publishing; Reader; Research Project Grants; Research Proposals; Role; Shapes; Site; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Ubiquitin; cancer risk; cell type; chromatin remodeling; cohort; cost; gamma-Glutamyl Hydrolase; graduate student; histone methylation; improved; loved ones; novel; p53-binding protein 1; protein function; recruit; replication stress; ubiquitin isopeptidase; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, hematologic disease and bone marrow failure, increased cancer risk, and premature mortality. Therapeutic options for FA are extremely limited and the overall life expectancy of FA patients is only 29 years. The molecular etiology of FA is poorly understood and no rational therapeutic approaches based on the biochemistry of this disease have been developed. Consequently, the prognosis for FA patients - and their families and loved ones - is poor. Progress in this field will only be achieved by a greater understanding of the molecular basis of this disease, underscoring the significance of our proposed studies. FA is caused by mutations in any one of 23 genes. The FA proteins function to repair DNA damage and to maintain chromosome stability. A key step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA damaging agents. The monoubiquitination of FANCD2 and FANCI promotes their assembly into discrete chromatin-associated foci. The mechanisms by which FANCD2 and FANCI are targeted to, retained in, and function within chromatin are, however, largely unknown. Importantly, FANCD2 and FANCI monoubiquitination is defective in >90% of FA patients and integral to FA patient BMF and hematologic disease. The overarching goal of our 3-year SHINE II R01 research proposal (parent award) is to elucidate the molecular underpinnings of the connections between FA and chromatin plasticity. Directly related to this goal, we propose that FANCD2 regulates the expression of select large transcriptionally active units under conditions of replication stress. We further speculate that the cohort of FANCD2-regulated large genes will be cell-type specific. The major goals of this Graduate Student Diversity Supplement are to directly test these hypotheses. Our studies have the potential to open a new avenue of therapeutic intervention for FA.

项目摘要/摘要 范可尼贫血(FA)是一种遗传性疾病，其特征是先天性异常、血液系统疾病和 骨髓衰竭、癌症风险增加和过早死亡。FA的治疗选择是极其重要的 而且FA患者的总体预期寿命只有29岁。FA的分子病因学较差 目前还没有基于这种疾病的生物化学的合理的治疗方法 发展起来的。因此，FA患者及其家人和亲人的预后很差。进展 只有更好地了解这种疾病的分子基础，才能在这一领域实现这一目标， 强调了我们提议的研究的重要性。 FA是由23个基因中的任何一个基因突变引起的。FA蛋白的功能是修复DNA损伤并 保持染色体稳定。FA途径激活的一个关键步骤是单素化 FANCD2和FANCI蛋白，暴露于DNA损伤剂时发生。单素化 FANCD2和FANCI的结合促进它们组装成离散的染色质相关焦点。这些机制由 然而，FANCD2和FANCI的靶向、保留在染色质中以及在染色质中起作用的主要是 未知。重要的是，FANCD2和FANCI在90%的FA患者中是有缺陷的。 对于FA患者的BMF和血液病是不可或缺的。 我们为期3年的SHARE II R01研究计划(家长奖)的首要目标是阐明 FA和染色质可塑性之间联系的分子基础。与这个目标直接相关， 我们认为，FANCD2调控选择的大转录活性单位的表达在 复制胁迫的条件。我们进一步推测，FANCD2调控的大基因队列将是 特定于单元格类型。这本研究生多样性补充手册的主要目标是直接测试这些 假设。我们的研究有可能为FA的治疗干预开辟新的途径。