TGF beta Pathway Inhibitors Rescue the Growth of Fanconi Anemia Primary Cells

TGF β 通路抑制剂可挽救范可尼贫血原代细胞的生长

基本信息

批准号：
9148333
负责人：
ALAN D. D'ANDREA
金额：
$ 44.66万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9148333
关键词：
Accounting Acetaldehyde Acute Myelocytic Leukemia Aplastic Anemia Apoptosis BRCA2 gene Binding Biochemical Bone Marrow Bone Marrow Cells Bone Marrow Diseases Bone Marrow Suppression Bone Marrow Transplantation Cell Cycle Cells Cellular biology Characteristics Chromosomal Instability Clinical Trials Clonal Evolution Collaborations Complex Congenital Abnormality Coupled Crosslinker DNA Crosslinking Agent DNA Damage DNA Repair DNA Repair Disorder DNA Repair Pathway DNA crosslink Data Defect Development Disease Disease Progression Dysmyelopoietic Syndromes Engraftment Excision Fanconi Anemia pathway Fanconi Anemia-BRCA Pathway Fanconi anemia protein Fanconi&apos s Anemia Functional disorder Genes Genetic Goals Grant Growth Hematopoietic Hematopoietic stem cells Human Hypersensitivity Inherited Laboratories Ligands Limb structure Malignant - descriptor Malignant Neoplasms Mediating Modeling Monoclonal Antibodies Mus Mutation Nonhomologous DNA End Joining Pancytopenia Pathway interactions Patients Phenotype Population Predisposition Premalignant Probability Proteins Rare Diseases Regulation Role Signal Pathway Signal Transduction Site Stem cells TP53 gene Toxic effect Transforming Growth Factor beta Transplantation Ubiquitin Umbilical Cord Blood cell growth crosslink endonuclease gene product homologous recombination improved in vitro Assay in vivo inhibitor/antagonist knock-down malignant breast neoplasm mouse model novel novel strategies pre-clinical programs receptor recombinational repair repaired skeletal small hairpin RNA small molecule small molecule inhibitor stem transcription factor

项目摘要

PROJECT 2 PROJECT SUMMARY: Fanconi Anemia (FA) is an inherited DNA repair disorder characterized by congenital abnormalities, cancer predisposition, and progressive bone marrow failure. FA is caused by biallelic mutations in one of sixteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway. Although the precise biochemical functions of the FA/BRCA pathway remain unclear, the pathway promotes homologous recombination (HR) repair. Due to the underlying DNA repair defect, FA cells are hypersensitive to genotoxic DNA crosslinking agents. The mechanism of the bone marrow failure (BMF) in FA remains elusive. Our recent studies suggest that BMF results, at least in part, from increased p53 expression in hematopoietic stem and progenitor cells (HSCPs), leading to progressive cell cycle delay and apoptosis. BMF may also result from the accumulation of DNA damage from the endogenous crosslinking agent, acetaldehyde, and the selective toxicity of this agent to hematopoietic stem cells. Recently, we identified hyperactive TGFβ signaling as a mechanism of bone marrow suppression in FA. Disruption of TGFβ signaling, through the use of shRNAs, sgRNAs, and small molecule inhibitors confirmed the suppressive role of the pathway on FA cell growth. We hypothesize that an upstream inhibitor of the TGFβ pathway (i.e., a monoclonal antibody to TGFβ itself) will inhibit this pathway and rescue the function of the HSPCs, resulting in an increased probability of rescuing bone marrow function in FA patients. It is possible that TGFβ inhibitors may also promote the clonal evolution of premalignant or malignant hematopoietic stem cell. The specific aims of Project 2 are: 1) determine the mechanism by which TGF-β inhibitors promote FA cellular growth and regulate DNA repair, 2) to determine whether inhibition of TGF-β pathway rescues hematopoietic defects in FA mouse models, and 3) to determine whether inhibition of TGF-β pathway rescues hematopoietic defects in primary bone marrow cells from FA patients. Project 2 will interact extensively with Project 1 (Grompe), which will analyze other small molecules capable of improving FA cell growth and Project 3 (Shimamura), which will analyze the effect of these small molecules on primary human FA cells and will provide additional preclinical data for an FA clinical trial. The projects will utilize four Core programs, as described in the accompanying Core components.

项目 2 项目摘要：范可尼贫血 (FA) 是一种遗传性 DNA 修复障碍，其特征是先天性异常、癌症易感性和进行性骨髓衰竭是由十六种之一的双等位基因突变引起的。 FANC 基因，其产物在 FA/BRCA DNA 修复途径中协同作用。 FA/BRCA通路的生化功能尚不清楚，该通路促进同源由于潜在的 DNA 修复缺陷，FA 细胞对基因毒性高度敏感。 DNA 交联剂。我们最近对 FA 骨髓衰竭 (BMF) 的机制仍不清楚。研究表明，BMF 至少部分是由于造血干细胞中 p53 表达增加所致祖细胞（HSCP），导致进行性细胞周期延迟和细胞凋亡也可能是由内源性交联剂乙醛和选择性交联剂造成的 DNA 损伤的积累最近，我们发现过度活跃的 TGFβ 信号传导是一种对造血干细胞的毒性。 FA 中骨髓抑制的机制，通过使用 shRNA 破坏 TGFβ 信号传导， sgRNA 和小分子抑制剂证实了该途径对 FA 细胞生长的抑制作用。随后 TGFβ 途径的上游抑制剂（即 TGFβ 本身的单克隆抗体）将抑制该通路并挽救 HSPC 的功能，从而增加挽救的可能性 FA 患者的骨髓功能 TGFβ 抑制剂也可能促进克隆进化。项目2的具体目标是：1）确定癌前或恶性造血干细胞。 TGF-β抑制剂促进FA细胞生长和调节DNA修复的机制，2) 确定抑制 TGF-β 通路是否可以挽救 FA 小鼠模型中的造血缺陷，以及 3) 确定抑制 TGF-β 通路是否可以挽救 FA 原代骨髓细胞的造血缺陷项目 2 将主要与项目 1 (Grompe) 相互作用，项目 1 将分析其他小分子。能够改善 FA 细胞生长和项目 3（Shimamura），该项目将分析这些小细胞的影响原代人类 FA 细胞上的分子，将为 FA 临床试验提供额外的临床前数据。项目将利用四个核心程序，如随附的核心组件中所述。