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

呼吸窘迫婴儿 SP-C 和关键 UPR 基因的变异

• 批准号: 7394675
• 负责人: Jennifer Wambach
• 金额: $ 2.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394675
• 关键词: Age of Onset; Alleles; Alveolar; Biometry; C-Peptide; Clinical; Complex Mixtures; Computer Analysis; DNA; DNA Resequencing; Data; Disease; Disruption; Doctor of Medicine; Endoplasmic Reticulum; Exons; Frequencies; Future; Gene Components; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Grant; Homeostasis; Human; Infant; Introns; Laboratories; Logistic Regressions; Lung; Lung diseases; Methods; Mutation; Neonatal; Newborn Infant; Newborn Respiratory Distress Syndrome; Pathway interactions; Patient Care; Patients; Phenotype; Phospholipids; Postdoctoral Individual National Research Service Award; Pregnancy; Principal Investigator; Process; Protein Biosynthesis; Protein C; Proteins; Pulmonary Surfactants; Quality Control; RNA; Race; Research; Respiratory distress; Risk; Sampling; Severities; Signal Pathway; Statistical Methods; Structure; Surface Tension; Thinking; Training; Translations; Universities; Variant; Washington; Week; alveolar type II cell; base; experience; expiration; genetic epidemiology; genetic regulatory protein; insight; practical application; programs; promoter; protein folding; response; skills; surfactant

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.

描述（由申请方提供）：表面活性剂蛋白C（SP-C）是一种肺特异性疏水蛋白。在表面活性蛋白C基因（SFTPC）中已经确定了超过35个单等位基因突变，这些突变导致从新生儿期到成年期不同严重程度和发病年龄的呼吸道疾病。与SFTPC突变相关的肺部疾病被认为是由错误折叠或错误推定的proSP-C肽聚集引起的，这些肽未能被加工成成熟形式，压倒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由多种细胞内信号传导途径组成，其通过减少一般RNA翻译来减少蛋白质合成，增加累积蛋白质的降解，并增加内质网（ER）的蛋白质折叠和分泌能力。理论上，UPR的任何组分的失调都可能改变其维持细胞稳态的能力，并可能揭示SFTPC中变体的表达。因此，这一提议的假设是，SFTPC的变体和未折叠蛋白反应的组分相互作用，增加新生儿肺部疾病的风险和严重程度。第一个目的是使用完全重测序来确定500例种族匹配的RDS患者和非RDS患者的SFTPC基因变异的基于表型的频率，并确定RDS婴儿中是否存在先前未识别的或其他潜在的重要变异。第二个目标是使用Illumina tagSNPs面板确定7个关键基因中基于表型的变体频率，这些关键基因编码相同500名患者的未折叠蛋白质反应的调节因子。最后，第三个目的是使用序贯逻辑回归研究SFTPC变异体与UPR基因的相互作用，这些基因增加了RDS的风险。