Variation in SP-C and Key UPR Genes among Infants with Respiratory Distress

描述(由申请人提供)：表面活性蛋白C(SP-C)是一种肺特异的疏水蛋白。已在表面活性蛋白C基因(SFTPC)中发现了超过35个单等位基因突变，这些突变会导致从新生儿到成年的不同严重程度和发病年龄的呼吸系统疾病。与SFTPC突变相关的肺部疾病被认为是由于错误折叠或错误的Prosp-C多肽聚集导致的，这些多肽未能加工成成熟形式，淹没了细胞质量控制途径的能力，并激活了未折叠蛋白反应(UPR)。UPR由多个细胞内信号通路组成，这些信号通路通过减少一般RNA的翻译来减少蛋白质的合成，增加积累的蛋白质的降解，并增加内质网(ER)的蛋白质折叠和分泌能力。从理论上讲，UPR任何成分的失调都可能改变其维持细胞内稳态的能力，并可能揭示SFTPC中变体的表达。因此，这项建议的假设是SFTPC的变异和未折叠蛋白反应的组成部分相互作用，增加了新生儿肺部疾病的风险和严重程度。第一个目标是使用完全重测序来确定500名患有和不患有RDS的种族匹配患者SFTPC基因变异的表型频率，并确定在患有RDS的婴儿中是否存在以前未识别的或其他潜在的重要变异。第二个目标是使用Illumina标签SNPs小组来确定这500名患者中编码未折叠蛋白反应调节因子的七个关键基因的基于表型的变异频率。最后，第三个目标是使用序贯Logistic回归分析SFTPC变异与UPR基因之间的相互作用，以增加RDS的风险。

DESCRIPTION (provided by applicant): Surfactant protein C (SP-C) is a lung specific, hydrophobic protein. Over 35 single allelic mutations have been identified in the surfactant protein C gene (SFTPC) that cause respiratory disease of varying severity and age of onset from the newborn period to adulthood. The lung disease associated with mutations in SFTPC is thought to result from aggregation of misfolded or misrputed proSP-C peptides that fail to be processed into the mature form, overwhelm the capacity of cellular quality control pathways, and activate the unfolded protein response (UPR). The UPR consists of multiple intracellular signaling pathways that decrease protein synthesis by decreasing general RNA translation, increase degradation of accumulated proteins, and increase the protein folding and secretion capacity of the endoplasmic reticulum (ER). Theoretically, dysregulation of any component of the UPR may alter its capacity to maintain cellular homeostasis and may unmask expression of variants in SFTPC. Thus, the hypothesis of this proposal is that variants in SFTPC and components of the unfolded protein response interact to increase the risk and severity of lung disease in newborns. The first aim is to use complete resequencing to determine the phenotype-based frequency of variants of the SFTPC gene for 500 race-matched patients with and without RDS and to identify whether previously unrecognized or other potentially significant variants are present in infants with RDS. The second aim is to determine a phenotype-based frequency of variants in seven of the key genes that encode regulatory factors of the unfolded protein response for these same 500 patients using an Illumina panel of tagSNPs. Finally, the third aim is to look at the interaction of SFTPC variants with genes of the UPR that increase the risk for RDS using sequential logistic regression.