Functional Identification of Genes Mutated in FHLH

FHLH 突变基因的功能鉴定

基本信息

批准号：
7533363
负责人：
Janos Sumegi
金额：
$ 21.4万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533363
关键词：
Accounting Affect Algorithms Allogeneic Bone Marrow Transplantation Apoptosis Biological Assay Candidate Disease Gene Cell physiology Cells Cellular biology Chromosomes Chromosomes, Human, Pair 9 Code Collection Critical Pathways Cytoplasmic Granules Cytotoxic T-Lymphocytes Data Defect Development Diagnosis Disease Dissection Double-Stranded RNA Exocytosis Family Gene Family Gene Frequency Gene Targeting Genes Genetic Genome Genomics Human Immune Immunologic Deficiency Syndromes Individual Inflammatory Response Left Link Localized Disease Lytic Maps Mediating Membrane Messenger RNA Mutate Mutation Natural Killer Cells Numbers Pathologic Patients Phospholipids Population Predisposition Process Protein Family Proteins Public Health RNA Decay RNA Interference RNA Processing Recessive Genes Request for Proposals Research Personnel Research Project Grants SNAP receptor T-Lymphocyte Testing UNC13B gene base cytotoxic design familial hemophagocytic lymphohistiocytosis genetic analysis genetic linkage analysis member perforin prevent receptor response small hairpin RNA syntaxin 11

项目摘要

DESCRIPTION (provided by applicant): Familial Hemophagocytic Lymphohistiocytosis (FHLH) is almost universally fatal unless aggressively treated soon after diagnosis, and corrected with allogeneic bone marrow transplantation. All forms of FHLH likely result from genetic defects in the natural down regulating mechanisms of immune/inflammatory responses. Three autosomal recessive gene defects underlie 40-50% of primary (familial) cases worldwide: perforin (20-30%), the major immune cytotoxic protein, MUNC 13- 4 (20%), a protein involved in exocytosis of perforin-bearing cytotoxic granules during apoptosis and STX11, member of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). Thus in more than half of the FHLH cases, the affected individuals have other as yet unknown genetic alterations. The classic genetic approach to identify these genes, through linkage analysis, has limitations because linkage analysis often leave investigators confronting broad genomic regions containing hundred of genes. Factors such as the impracticality of dramatically increasing the number of families tested, low allelic frequency, and the rarity of families with the disease often prevent the statistical narrowing down of these large regions to identify the involved gene. In this study, we propose a cell-biology-based approach to accelerate the dissection of FHLH susceptibility loci. Our strategy utilizes RNA interference (RNAi), the process where double-stranded RNA induces the homology-dependent degradation of cognate mRNA. The RNAi strategy will be used to identify candidate genes in lymphohistiocytosis susceptibility region on chromosome 9q21.3-22 and among genes coding for SNARE proteins essential for direct, controlled, and very rapid fusion of phospholipids membranes. PUBLIC HEALTH RELEVANCE: Familial Hemophagocytic Lymphohisticytosis, disease genes, identification, microarray, nonsense mediated mRNA decay, RNA interference, SNAREs.

描述（由申请人提供）：除非在诊断后尽快进行积极治疗，并通过同种异体骨髓移植纠正，否则家族性血有淋巴细胞吞噬作用（FHLH）几乎是致命的。所有形式的FHLH可能是由于自然下降调节免疫/炎症反应机制的遗传缺陷而导致的。全世界40-50％的原发性（家族）病例的三个常染色体隐性基因缺陷是40-50％的基础：培养蛋白（20-30％），主要的免疫细胞毒性蛋白，MUNC 13-4（20％）（20％），一种蛋白质，蛋白质参与含氧蛋白含量的细胞毒性毒性剂量的蛋白质，在磷灰蛋白蛋白质的蛋白质和St剂量固定剂中，溶于磷脂的植物植物剂量的成员 - 受体（军鼓）。因此，在超过一半的FHLH病例中，受影响的个体具有其他尚不清楚的遗传改变。通过连锁分析，鉴定这些基因的经典遗传方法具有局限性，因为连锁分析通常会使研究人员面对含数百个基因的广泛基因组区域。诸如不切实际的因素急剧增加了测试的家庭数量，低等位基因频率以及患有该疾病的家庭的稀有性，通常会阻止这些大区域的统计学缩小以识别所涉及的基因。在这项研究中，我们提出了一种基于细胞生物的方法来加速FHLH易感基因座的解剖。我们的策略利用了RNA干扰（RNAI），该过程是双链RNA诱导同源性mRNA的同源性降解的过程。 RNAi策略将用于鉴定染色体9q21.3-22上淋巴组织细胞增多症易感区域的候选基因以及编码磷脂膜的直接，控制和非常快速融合所必需的SNARE蛋白的基因中。公共卫生相关性：家族性肉质细胞淋巴细胞增多症，疾病基因，鉴定，微阵列，胡说八道介导的mRNA衰变，RNA干扰，SNARES。