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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/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 的治疗选择非常多 FA 患者的总体预期寿命有限，仅为 29 岁。 FA 的分子病因学尚不明确目前尚无基于该疾病生物化学的合理治疗方法发达。因此，FA 患者及其家人和亲人的预后很差。进步只有更好地了解这种疾病的分子基础才能实现这一领域的目标，强调我们提出的研究的重要性。 FA 是由 23 个基因中任何一个的突变引起的。 FA 蛋白的功能是修复 DNA 损伤并维持染色体稳定性。 FA途径激活的关键步骤是单泛素化 FANCD2 和 FANCI 蛋白，在接触 DNA 损伤剂时出现。单泛素化 FANCD2 和 FANCI 的结合促进它们组装成离散的染色质相关灶。其机制由然而，FANCD2 和 FANCI 在染色质中的靶向、保留和功能在很大程度上是未知。重要的是，FANCD2 和 FANCI 单泛素化在 90% 以上的 FA 患者中存在缺陷，并且 FA 患者 BMF 和血液疾病的组成部分。我们为期 3 年的 SHINE II R01 研究计划（母奖）的总体目标是阐明 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的是，我们认为 FANCD2 在以下条件下调节选定的大转录活性单位的表达复制压力的条件。我们进一步推测 FANCD2 调控的大基因队列将是细胞类型特异性。本研究生多样性补充材料的主要目标是直接测试这些假设。我们的研究有可能为 FA 治疗干预开辟一条新途径。