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

• 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
• 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' 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

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： Fanconi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。 FA是由16个中的双重突变引起的 FANC基因，其产品在FA/BRCA DNA维修途径中进行了教练。虽然是精度 FA/BRCA途径的生化功能尚不清楚，该途径促进了同源 重组（HR）修复。由于潜在的DNA修复缺陷，FA细胞对遗传毒素过敏 DNA交联剂。 FA中骨髓衰竭（BMF）的机制仍然难以捉摸。我们的最新消息 研究表明，BMF至少部分是由于造血茎中的p53表达增加而结果 祖细胞（HSCP），导致进行性细胞周期延迟和凋亡。 BMF也可能是由 内源交联剂乙醛和选择性的DNA损伤积累 该药物对造血干细胞的毒性。最近，我们确定了多动性TGFβ信号作为A FA中骨髓抑制的机理。通过使用shRNA的破坏TGFβ信号传导， SGRNA和小分子抑制剂证实了该途径在FA细胞生长中的抑制作用。我们 假设TGFβ途径的上游抑制剂（即，与TGFβ本身的单克隆抗体） 抑制这一途径并拯救HSPC的功能，从而增加了营救的可能性 FA患者的骨髓功能。 TGFβ抑制剂可能也可能促进克隆进化 前造血干细胞或恶性造血干细胞的。项目2的具体目的是：1）确定 TGF-β抑制剂促进FA细胞生长并调节DNA修复的机制，2） TGF-β途径的抑制是否可以挽救FA小鼠模型中的造血缺陷，并确定3） TGF-β途径的抑制是否可以从FA中挽救原代骨髓细胞中的造血缺陷 患者。项目2将与项目1（grompe）广泛相互作用，该项目将分析其他小分子 能够改善FA细胞生长和项目3（Shimamura），这将分析这些小的效果 原代人FA细胞上的分子，将为FA临床试验提供其他临床前数据。这 如参与的核心组件中所述，项目将利用四个核心程序。