The Role of surfactant protein genetic variants in cyst*

描述(申请人提供)：我们的长期目标是研究修饰基因 影响囊性纤维化(CF)患者肺部疾病严重程度 重点介绍肺产生的表面活性蛋白(SP-) 上皮细胞。SP-A和SP-D在固有的主机防御和/或 肺内炎症过程的调节，而SP-B是必不可少的 以恢复正常的肺功能。初步研究表明，SP-A基因 变异与慢性萎缩性胃炎的严重程度有关。总体上的理由是 对于拟议的研究来说，存在着显著的异质性 慢性阻塞性肺疾病患者的肺部疾病严重程度，即使在那些 纤维蛋白原跨膜电导F508突变的纯合子 调节基因(Cftr)。这种表型多样性可能与 表面活性物质蛋白基因的遗传异质性。中国的遗传变异 SP-B基因可能与肺功能和遗传物质的差异有关 SP-A和SP-D的变化可能与宿主天然防御系统的差异有关 在CF中的功能。总体假设表明，SP-A、SP-B和SP-D是 CF中肺部疾病严重程度的修饰物及其之间的差异 SP-A基因变异体调节假单胞菌吞噬功能的研究 铜绿假单胞菌。在这项建议中，我们将开展两大组 实验。一是深入开展家庭联谊会研究。 扩展传输不平衡检验(ETDT)和/或TDT分析， SP-A、SP-B和SP-D标记基因座，以及Cf，以确定这些基因座是否 与CF连锁，并确定CF严重程度的易感SP等位基因。这个 整个CF研究组以及基于CFTR型的多个子组， 将对严重性或其他标准进行研究。Logistic回归分析 将用于确定在CF中可能具有特殊重要性的因素 以及特定的基因类型(目标1)。在第二组实验中，我们 将专注于SP-A基因变种，其初步证据表明 SP-A等位基因与CF严重程度之间存在关联。我们会研究 SP-A等位基因增强吞噬功能的能力差异 粘液型和非粘液型P。 已经证明在不同环境条件下生长的铜绿假单胞菌 复制某些生物化学和功能特性 铜绿假单胞菌临床分离株(AIM 2)及粘液型和非粘液型 慢性萎缩性胃炎患者铜绿假单胞菌分离株(目标3) 这些发现可能有助于识别特定的宿主防御机制，包括 等位基因与CF的肺部疾病严重程度相关，并发展为有用的 体外模型研究铜绿假单胞菌及其在体内的修饰 并为进一步考虑小说提供了基础 治疗慢性肺纤维化相关肺部疾病的治疗策略。

DESCRIPTION (provided by applicant): Our long-term objectives are to study mechanisms by which modifier genes affect pulmonary disease severity in patients with cystic fibrosis (CF), with emphasis on the surfactant proteins (SP-), which are produced by lung epithelial cells. SP-A and SP-D play a role in the innate host defense and/or the regulation of inflammatory processes in the lung, and SP-B is essential for normal lung function. Preliminary findings indicate that SP-A genetic variants are associated with disease severity in CF. The overall rationale for the proposed studies is that significant heterogeneity exists in the severity of pulmonary disease in CF patients, even in those that are homozygous for the F508 mutation of the CF transmembrane conductance regulator gene (CFTR). This phenotypic diversity may be related to the genetic heterogeneity of the surfactant protein genes. Genetic variation in the SP-B gene may relate to differences in pulmonary function and genetic variation in SP-A and SP-D may relate to differences in innate host defense function in CF. The overall hypothesis states that SP-A, SP-B, and SP-D are modifiers of pulmonary disease severity in CF and that differences exist among SP-A genetic variants in their ability to modulate phagocytosis of Pseudomonas aeruginosa. In this proposal, we will carry out two major groups of experiments. First, we will study family-based associations by carrying out extended transmission disequilibrium test (ETDT) and/or TDT analyses, of the SP-A, SP-B, and SP-D marker loci, and CF, to determine whether these loci are linked to CF and identify susceptibility SP alleles for CF severity. The entire CF study group as well as a number of subgroups based on CFTR genotype, severity, or other criteria, will be studied. Logistic regression analysis will be used to identify factors that may be of particular significance in CF along with specific genotypes (Aim 1). In the second group of experiments, we will focus on SP-A genetic variants for which preliminary evidence of an association between SP-A alleles and CF severity exists. We will study differences in the ability of SP-A alleles to enhance phagocytosis, by a macrophage-like cell line, of laboratory strains of mucoid and non-mucoid P. aeruginosa grown under different environmental conditions that have been shown to reproduce certain biochemical and functional characteristics found in clinical isolates of P. aeruginosa (Aim 2) and of mucoid and non-mucoid isolates of P. aeruginosa from CF patients (Aim 3). The findings may help identify specific host defense mechanisms involving alleles associated with pulmonary disease severity in CF and develop a useful in vitro model to study the in vivo modifications of P. aeruginosa and its clearance, and provide the basis for further consideration of novel therapeutic strategies to treat CF-related lung disease.