Genetics of Autoimmune Hemolytic Anemia

自身免疫性溶血性贫血的遗传学

基本信息

批准号：
8707841
负责人：
DWIGHT H KONO
金额：
$ 46.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707841
关键词：
Advanced Development Affect Antibodies Antibody Formation Antigens Ants Autoimmune Diseases Autoimmune hemolytic anemia Autoimmunity B-Cell Activation Cell physiology Characteristics Chromosomes, Human, Pair 17 Chromosomes, Human, Pair 4 Code Congenic Mice Congenic Strain Defect Detection Disease Erythrocytes Functional RNA Functional disorder Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genome Goals Hemolytic Anemia Hereditary Disease High-Throughput Nucleotide Sequencing Immunoglobulins Inbred NZB Mice Individual Knowledge Lead Link Location Lupus Maps Modeling Mus Mutation NZW Mouse Names Nature Nuclear Nucleotides Pathogenesis Patients Phenotype Play Population Predisposition Reporting Role Splenomegaly Susceptibility Gene Systemic Lupus Erythematosus Variant base gene function genetic variant genome sequencing human disease insight novel novel strategies protein function protein structure public health relevance research study response structural genomics trait

项目摘要

DESCRIPTION (provided by applicant): It is well established that genetic predisposition plays a major role in the susceptibility of individuals to systemic lupus erythematosus (SLE). Therefore, definition of the causal mechanisms responsible for this disease will require knowledge of both the genetic alterations and the nature of their contribution to autoimmunity. We have previously identified in (NZBxNZW)F2 mice eight loci designated Lbw1-8 on chromosomes 17, 4, 5, 6, 7, 18, 1 and 11, respectively, that were linked to one or more SLE disease traits. Interval-specific congenic strains for Lbw2 been generated and the specific component phenotypes have been identified. Notably, NZB.NZW-Lbw2 interval congenic mice demonstrated a marked reduction in autoimmune hemolytic anemia (AIHA) and consequent splenomegaly that was not associated with defects in immunoglobulin levels, anti-nuclear antibodies, or B cell activation. Using subcongenic mice it was further revealed that Lbw2 contained at least three loci affecting AIHA. This proposal will use a novel whole genome sequencing approach to first identify predicted genetic variants that affect gene function either by altering protein structure or modifying gene expression, and then identify the most likely candidate 'functional' variant within Lbw2 subloci. This proposal has two specific aims. The first will identify coding-region candidate variants for Lbw2 and other lupus-affecting loci based on the whole genome sequences of the NZB and NZW mice. The second aim will use the information from aim 1 to further evaluate the coding-region candidate variants, to identify non-coding candidate variants, and to define the mechanisms by which the Lbw2 locus- related variants promote antibodies to RBC. Identification of the susceptibility genes and elucidation of their roles in the induction of lupus should provide significant insights into the etiopathogenesis of genetically- determined autoimmune diseases.

描述（由申请人提供）：众所周知，遗传易感性在个体对系统性红斑狼疮（SLE）的易感性中起着重要作用。因此，定义导致这种疾病的因果机制需要了解遗传改变及其对自身免疫的贡献的性质。我们之前在 (NZBxNZW)F2 小鼠中鉴定了 8 个位点，分别位于 17、4、5、6、7、18、1 和 11 号染色体上，称为 Lbw1-8，它们与一种或多种 SLE 疾病特征相关。 Lbw2 的区间特异性同源菌株已产生，并且特定成分表型已被鉴定。值得注意的是，NZB.NZW-Lbw2 间期同系小鼠表现出自身免疫性溶血性贫血 (AIHA) 和随之而来的脾肿大的显着减少，这与免疫球蛋白水平、抗核抗体或 B 细胞激活缺陷无关。使用亚同类小鼠进一步揭示 Lbw2 包含至少三个影响 AIHA 的基因座。该提案将使用一种新颖的全基因组测序方法，首先识别通过改变蛋白质结构或修改基因表达来影响基因功能的预测遗传变异，然后识别 Lbw2 亚位点中最有可能的候选“功能”变异。该提案有两个具体目标。第一个将根据 NZB 和 NZW 小鼠的全基因组序列识别 Lbw2 和其他狼疮影响基因座的编码区候选变体。第二个目标将使用目标 1 中的信息进一步评估编码区候选变体，识别非编码候选变体，并定义 Lbw2 位点相关变体促进 RBC 抗体的机制。易感基因的鉴定并阐明它们在狼疮诱导中的作用将为了解狼疮的发病机制提供重要的见解遗传决定的自身免疫性疾病。