The Role of surfactant protein genetic variants in cyst*

描述（由申请人提供）： 我们的长期目标是研究修饰基因 影响囊性纤维化（CF）患者的肺部疾病严重程度， 强调肺产生的表面活性蛋白（SP-） 上皮细胞 SP-A和SP-D在先天宿主防御和/或免疫应答中起作用。 调节肺部的炎症过程，SP-B是必不可少的 正常的肺功能 初步研究结果表明，SP-A基因 变异与CF中的疾病严重程度相关。 总体理由 对于拟议的研究是，显着的异质性存在于 CF患者中肺部疾病的严重程度，即使在那些 CF跨膜传导的F508突变纯合子 调节基因（CFTR）。 这种表型多样性可能与 表面活性蛋白基因的遗传异质性。 遗传变异 SP-B基因可能与肺功能和遗传差异有关 SP-A和SP-D的变异可能与宿主先天防御的差异有关 功能在CF。 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符， SP-A遗传变异体调节假单胞菌吞噬作用的能力 铜绿。 在本建议中，我们将开展两大类活动， 实验 首先，我们将研究以家庭为基础的协会， 扩展传递不平衡检验（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是 与CF相关，并鉴定CF严重程度的易感性SP等位基因。 的 整个CF研究组以及基于CFTR基因型的许多亚组， 将研究严重性或其他标准。 Logistic回归分析 将用于识别可能在CF中具有特殊意义的因素 沿着特定基因型（目的1）。 在第二组实验中，我们 将重点关注SP-A基因变异，初步证据表明， SP-A等位基因与CF严重程度之间存在关联。 我们将研究 SP-A等位基因增强吞噬作用的能力差异， 巨噬细胞样细胞系，粘液和非粘液P. 在不同的环境条件下生长的铜绿， 来复制某些生物化学和功能特性， 铜绿假单胞菌（Aim 2）以及粘液和非粘液的临床分离株 从CF患者分离的铜绿假单胞菌（目的3）。 这些发现可能有助于确定特定的宿主防御机制， CF中与肺部疾病严重程度相关的等位基因，并开发一种有用的 研究铜绿假单胞菌的体内修饰及其在体外的应用 清除，并为进一步审议新的 治疗CF相关肺病的治疗策略。

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.