Insights from somatic genomics lead to novel therapeutic targets in inherited bone marrow failure syndromes: Shwachman-Diamond Syndrome as a model.

体细胞基因组学的见解带来了遗传性骨髓衰竭综合征的新治疗靶点：以 Shwachman-Diamond 综合征为模型。

• 批准号: 10425437
• 负责人: Alyssa Kennedy
• 金额: $ 13.49万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425437
• 关键词: Academic Training; Address; Architecture; Award; Bar Codes; Binding; Bone Marrow; Bone marrow failure; Boston; Bypass; Cancer Hospital; Catalysis; Cells; Cellular Stress; Childhood; Clinical Research; Clonal Evolution; Computational Biology; DNA; DNA sequencing; Data; Defect; Development Plans; Disease; Dysmyelopoietic Syndromes; Excision; Fibroblasts; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Grant; Guanosine Triphosphate Phosphohydrolases; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immunophenotyping; Inherited; Institutes; Institution; Laboratories; Lead; Leadership; Location; Marrow; Mediating; Medical; Mentors; Missense Mutation; Modeling; Molecular; Morbidity - disease rate; Mutation; Outcome; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Physicians; Predisposing Factor; Predisposition; Prognosis; Proteins; Proteomics; Recurrence; Reporting; Research; Ribosomes; Sampling; Scientist; Shwachman-Diamond syndrome; Somatic Mutation; Stress; Syndrome; TP53 gene; Testing; Therapeutic; Time; Training; Translating; Translations; Writing; base; bone marrow failure syndrome; career development; cohort; curative treatments; design; experimental study; fitness; genomic data; improved; in vitro Model; innovation; insight; loss of function; loss of function mutation; medical schools; mortality; new therapeutic target; novel; rational design; skills; therapeutic target; treatment strategy; young adult

PROJECT SUMMARY/ABSTRACT Inherited bone marrow failure syndromes are characterized by hematopoietic aplasia and predisposition to myelodysplasia. These disorders are underdiagnosed, and the only curative treatment is hematopoietic stem cell transplant. In order to understand the mechanisms that mediate bone marrow failure and clonal evolution, this proposal focuses on Shwachman-Diamond Syndrome (SDS), a bone marrow failure and MDS predisposition syndrome caused by biallelic mutations in the SBDS gene. This gene encodes a protein that regulates ribosome maturation. The SBDS protein specifically promotes formation of the mature, translationally active 80S ribosome by aiding in catalysis of removal of EIF6 from the 60S ribosomal subunit. Preliminary data presented in this proposal has identified recurrent and persistent somatic missense mutations in EIF6 and TP53 within the bone marrow of patients with SDS. The most common EIF6 mutation leads to a loss of function and abolishes EIF6 binding with the 60S ribosomal subunit and improves SDS cell fitness, identifying a novel target for SDS therapy. The central hypothesis of this proposal is that inherited bone marrow failure syndromes have decreased hematopoietic cell fitness determined by the inherited molecular defect and somatic mutations specifically rescue the underlying fitness defect or bypass cell stress pathways. The proposal addresses this hypothesis with the following specific aims: (1) Identify the hematopoietic cell of origin and hematopoietic consequences of EIF6 and TP53 somatic mutations in SDS. (2) Evaluate the disruption of the EIF6:60S interaction and decreased EIF6 protein stability in SDS. In the first aim, single cell DNA sequencing combined with DNA-barcoded immunophenotyping will be used to determine clonal architecture and a single cell genotype-phenotype of somatic mutations in the SDS bone marrow. In the second aim, rational de novo designed miniproteins will be used to interrogate EIF6:60S binding as a therapeutic strategy. Data generated from this study will inform the pathophysiology and treatment of SDS-associated bone marrow failure and can be applied to inform treatment of other bone marrow failure syndromes, the study of clonal hematopoiesis and ribosome maturation. A K08 award will provide the candidate with protected time to complete additional academic training in computational biology, somatic genomic analysis and high-throughput proteomics approaches. A detailed career development plan is proposed which will enable the candidate to attain additional scientific expertise noted above and training in grant-writing, leadership and management skills. The proposed studies will take place at the Dana- Farber/Boston Children's Hospital Cancer and Blood disorders center, an exemplary location to acquire additional training. The candidate has protected research time and strong institutional support. In addition, the candidate will have access to the Harvard Medical School-affiliated Broad Institute and Institute for Protein Innovation. These institutions are world renowned clinical and research centers that will enable the candidate to develop additional data and training to become an independent physician-scientist studying bone marrow failure.

项目总结/摘要 遗传性骨髓衰竭综合征的特征是造血发育不全和易患 脊髓发育不良这些疾病诊断不足，唯一的治愈性治疗是造血干细胞移植 细胞移植为了了解介导骨髓衰竭和克隆进化的机制， 该提案的重点是Shwachman-Diamond综合征（SDS），一种骨髓衰竭和MDS易感性 由SBDS基因双等位基因突变引起的综合征。该基因编码一种调节核糖体的蛋白 成熟SBDS蛋白特异性地促进成熟的、具有免疫活性的80 S核糖体的形成 通过帮助催化从60 S核糖体亚基去除EIF 6。初步数据显示， 一项提案确定了骨内EIF 6和TP 53的复发性和持续性体细胞错义突变 SDS患者的骨髓。最常见的EIF 6突变导致功能丧失并消除EIF 6 与60 S核糖体亚基结合并改善SDS细胞适应性，确定了SDS治疗的新靶点。 这一建议的中心假设是，遗传性骨髓衰竭综合征已经减少， 造血细胞适应性由遗传性分子缺陷和体细胞突变决定， 潜在的健康缺陷或旁路细胞压力途径。该提案针对这一假设， （1）鉴定造血细胞起源和EIF 6的造血后果， SDS中的TP 53体细胞突变。(2)评价EIF 6：60 S相互作用的破坏和EIF 6降低 SDS中的蛋白质稳定性。在第一个目标中，单细胞DNA测序与DNA条形码结合， 免疫表型将用于确定克隆结构和单细胞基因型-表型， SDS骨髓中的体细胞突变在第二个目标中，合理的从头设计的微蛋白将被 用于询问EIF 6：60 S结合作为治疗策略。本研究生成的数据将告知 SDS相关骨髓衰竭的病理生理学和治疗，并可用于指导治疗 其他骨髓衰竭综合征，克隆造血和核糖体成熟的研究。A K08 奖励将为候选人提供受保护的时间，以完成计算方面的额外学术培训 生物学、体细胞基因组分析和高通量蛋白质组学方法。详细的职业发展 提出了一项计划，使候选人能够获得上述额外的科学专门知识和培训 领导力和管理技能方面。拟议的研究将在达纳- 法伯/波士顿儿童医院癌症和血液疾病中心，是获得 额外的训练。候选人有保护的研究时间和强大的机构支持。此外该 候选人将有机会进入哈佛医学院附属的布罗德研究所和蛋白质研究所 创新这些机构是世界著名的临床和研究中心，将使候选人， 开发额外的数据和培训，成为一个独立的医生，科学家研究骨髓衰竭。