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Functional Analysis of RPL35A Alterations in Diamond Blackfan Anemia

钻石黑扇贫血症中 RPL35A 改变的功能分析

基本信息

批准号：
8451887
负责人：
Jason Eli Farrar
金额：
$ 13.43万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-26 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451887
关键词：
Adverse effects Advisory Committees Apoptosis Apoptotic Biogenesis Bone Marrow Cell Cycle Progression Cell Line Cell Lineage Cells Cellular Stress Response Cessation of life Characteristics Clinical Clinical Data Collaborations Complementary DNA Complex Congenital Abnormality Core Facility Defect Development Diagnosis Diamond-Blackfan anemia Disease Ensure Environment Erythroid Evaluation Family Foundations Frequencies Future Gene Abnormality Gene Proteins Generations Genetic Genetic Counseling Hematopoiesis Hematopoietic Human Inherited Inpatients Instruction Investigation Knock-out Laboratories Lead Link Malignant Neoplasms Mediating Mentors Messenger RNA Modeling Molecular Mus Mutation Myelogenous North America Pancytopenia Pathway interactions Patients Pattern Pediatric Hematology/Oncology Polyribosomes Predisposition Principal Investigator Program Development Protein Biosynthesis Protein Subunits Proteins Registries Research Resources Ribosomal Proteins Ribosomes Risk Role Sampling Small Interfering RNA Structural Protein Structure Surveys Syndrome Testing Transgenic Mice Translation Initiation Transplantation Validation Xenograft procedure base biological adaptation to stress career comparative comparative genomic hybridization effective therapy experience human disease improved knock-down leukemia microdeletion mouse model mutant novel progenitor programs protein expression research study screening small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines a 5-year program for the development of an academic research career in pediatric hematology/oncology. The principal investigator proposes to further his research experience and develop expertise in the mechanisms of inherited bone marrow failure syndromes through focused investigation of a novel pathway for the development of Diamond-Blackfan Anemia (DBA), a bone marrow failure syndrome that disrupts erythropoesis, leads to congenital abnormalities, and is a cancer-predisposition syndrome. This research program integrates extensive departmental and core facility resources at Johns Hopkins with the clinical resources of a national registry to provide a superb environment from which to develop an active and productive career in this field. Dr. Robert Arceci, a leader in pediatric hematology and oncology with expertise in abnormal myeloid development and molecular studies in leukemia, will sponsor and serve as chief mentor. Collaboration with the Diamond Blackfan Anemia Registry of North America (DEAR) will ensure access to critical patient samples and clinical data. An advisory committee of leaders in the fields of bone marrow failure, DBA and ribosome biogenesis will provide additional scientific and career mentoring. The research will focus on understanding the contribution of ribosomal protein abnormalities to the development of DBA through investigation of RPL35a, a large ribosomal subunit protein our laboratory identified as a novel cause of DBA. The specific aims are to: 1) delineate the types and frequency of ribosomal protein mutations and their associated clinical characteristics by sequencing for mutations and comparative genomic hybridization analysis to identify deletions, 2) determine the cellular consequences of RPL35a abnormalities to hematopoesis using an inducible lentiviral siRNA model in hematopoietic cell lines and bone marrow, and 3) determine the molecular consequences of RPL35a abnormalities by analysis of ribosome assembly/mRNA recruitment and protein expression changes. RELEVANCE (See instructions): . By carefully defining a new genetic cause of Diamond Blackfan anemia, these studies will improve the ability to diagnose and provide genetic counseling to at-risk families and may identify new targets for more effective treatments. This project will also have broader relevance in further defining the link between abnormalities of protein synthesis and bone marrow failure, birth defects, and cancer predisposition.

描述（由申请人提供）：本提案概述了一个为期5年的儿科血液学/肿瘤学学术研究职业发展计划。主要研究者建议通过集中调查Diamond-Blackfan贫血（DBA）发展的新途径，进一步丰富他的研究经验并发展遗传性骨髓衰竭综合征机制的专业知识，DBA是一种破坏红细胞生成的骨髓衰竭综合征，导致先天性异常，是一种癌症易感综合征。该研究计划将约翰霍普金斯广泛的部门和核心设施资源与国家登记处的临床资源相结合，为在该领域发展积极和富有成效的职业生涯提供了极好的环境。Robert Arceci博士是儿科血液学和肿瘤学的领导者，在异常骨髓发育和白血病分子研究方面具有专长，他将赞助并担任首席导师。与北美Diamond Blackfan贫血登记处（DEAR）的合作将确保获得关键患者样本和临床数据。一个由骨髓衰竭、DBA和核糖体生物发生领域的领导人组成的咨询委员会将提供额外的科学和职业指导。本研究将通过对RPL 35 a的研究，重点了解核糖体蛋白异常对DBA发展的贡献，RPL 35 a是我们实验室确定为DBA的新原因的核糖体大亚基蛋白。具体目标是：1）通过对突变进行测序和比较基因组杂交分析以鉴定缺失，描述核糖体蛋白突变的类型和频率及其相关的临床特征，2）在造血细胞系和骨髓中使用诱导型慢病毒siRNA模型确定RPL 35 a异常对造血的细胞后果，和3）通过分析核糖体组装/mRNA募集和蛋白质表达变化来确定RPL 35 a异常的分子后果。相关性（参见说明）：通过仔细定义Diamond Blackfan贫血的新遗传原因，这些研究将提高诊断和为高危家庭提供遗传咨询的能力，并可能确定更有效治疗的新靶点。该项目还将在进一步确定蛋白质合成异常与骨髓衰竭、出生缺陷和癌症易感性之间的联系方面具有更广泛的相关性。