Clonal Hematopoiesis in Diamond Blackfan Anemia

钻石黑扇贫血症的克隆性造血

基本信息

批准号：
8759862
负责人：
Wei Tong
金额：
$ 29.23万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-18 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759862
关键词：
Accounting Adverse effects Affect Anemia Applications Grants Bioinformatics Biopsy Blood Blood Cells Blood Transfusion Bone Marrow Bone Marrow Cells Candidate Disease Gene Cell Cycle Progression Cell Survival Cells Cleaved cell Clinical Clonal Evolution Clonal Expansion Clone Cells Congenital Anemia Constitutional Copy Number Polymorphism DNA DNA Sequence Data Defect Dependence Development Diamond-Blackfan anemia Disease Disease remission Drug Targeting Dysmorphology Environment Erythrocytes Family Family history of Family member Female Fibroblasts Funding Opportunities Gene Frequency Gene Mutation Genes Genetic Genome Genomics Goals Growth Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Individual Inherited Knowledge Loss of Heterozygosity Methodology Microarray Analysis Mononuclear Multipotent Stem Cells Mutate Mutation Nature Open Reading Frames Pancytopenia Parents Pathogenesis Pathology Patients Pattern Penetrance Persons Population Recording of previous events Research Ribosomal Proteins Sampling Sequence Analysis Severity of illness Silent Mutation Single Nucleotide Polymorphism Skin Somatic Mutation Spontaneous Remission Stem cell transplant Stem cells Steroids Syndrome Testing Thumb structure Transfusion Variant Work X Inactivation base clinical remission density disease-causing mutation erythroid differentiation exome sequencing genome-wide improved infancy insight mutation carrier precursor cell public health relevance research study response self-renewal therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure (BMF) syndrome that presents in infancy with red cell aplasia, sometimes with developmental abnormalities. In common with other (BMF) syndromes the BMF is variable and family members can carry the mutation but show mild or no BMF or, in other cases, patients can go into long lasting remission. We hypothesize that the variable penetrance and remission are due to somatic mutations in stem cells or multipotent progenitors that rescue cells from the effects of the inherited mutation, leading to clonal hematopoiesis and clinical remission. We believe that if we can determine the nature of these genetic changes they will increase our understanding of the pathogenesis of DBA and suggest potential drug targets that may be used in developing new treatments. We will isolate DNA from bone marrow and skin biopsies from 20 DBA patients, including some in clinical remission. We will determine genetic differences between the bone marrow sample and the skin sample from the same person to identify somatic mutations that have occurred in the bone marrow. This will be done using two approaches 1. High density SNP microarray analysis, to find genomic changes that will not be found by exome sequencing including copy number changes and acquisition of copy neutral loss of heterozygosity, where both copies of autosomal genes may derive from the same parent and 2. Whole exome sequencing to identify non-synonymous mutations in protein coding regions. Prior to functional studies, likely candidates for rescuing mutations will be further validated by re-sequencing in a second group of patients and bioinformatic analysis to assess their possible effects on hematopoiesis.

描述（由申请人提供）：戴蒙德·布莱克凡贫血（DBA）是一种遗传性骨髓衰竭（BMF）综合征，在婴儿期表现为红细胞再生障碍性贫血，有时伴有发育异常。与其他 (BMF) 综合征一样，BMF 是可变的，家庭成员可能携带突变，但表现出轻微或无 BMF，或者在其他情况下，患者可以进入长期缓解。我们假设不同的外显率和缓解是由于干细胞或多能祖细胞的体细胞突变所致，这些突变使细胞免受遗传突变的影响，从而导致克隆造血和临床缓解。我们相信，如果我们能够确定这些基因变化的性质，它们将增加我们对 DBA 发病机制的理解，并提出可用于开发新疗法的潜在药物靶点。我们将从 20 名 DBA 患者（包括一些临床缓解患者）的骨髓和皮肤活检中分离 DNA。我们将确定同一个人的骨髓样本和皮肤样本之间的遗传差异，以识别骨髓中发生的体细胞突变。这将使用两种方法来完成： 1. 高密度 SNP 微阵列分析，以发现外显子组测序无法发现的基因组变化，包括拷贝数变化和获得杂合性的拷贝中性丢失，其中常染色体基因的两个拷贝都可能源自同一亲本和 2. 全外显子组测序，以识别蛋白质编码区的非同义突变。在功能研究之前，可能的拯救突变候选者将通过对第二组患者进行重新测序和生物信息分析来进一步验证，以评估其对造血的可能影响。