Role of SFTPC in Pathogenesis of Interstitial Lung Disease

描述（由申请方提供）：特发性肺纤维化（IPF）是一种慢性、进行性间质性肺病（ILD），无有效治疗选择，诊断后平均生存期为3年。由于缺乏适当的动物模型，对该病的自然史了解甚少。家族性疾病占IPF总病例的不到5%，其特征为常染色体显性遗传，具有与遗传修饰剂和环境因素影响相关的可变遗传率。编码表面活性蛋白C（SP-C？外显子4和SP-CL 188 Q）提供了一个独特的机会，以确定潜在的家族性ILD的分子途径。我们在细胞培养中的初步研究已经确定了参与突变SP-C的检测和快速降解的独特分子复合物;此外，我们已经表明，表达突变SP-C并被呼吸道合胞病毒感染的细胞积累错误折叠的SP-C，并且比表达野生型蛋白的细胞更容易受到病毒诱导的细胞死亡的影响。这些关键的体外研究结果导致了一个中心假设，即叠加在SFTPC突变上的环境压力导致错误折叠的细胞毒性SP-C积累，进而导致2型上皮细胞损伤/死亡，这是SFTPC相关家族性ILD的诱发事件。提出了三个具体目标来检验这一假设：具体目标1将检验ERAD（一种细胞保护途径）快速识别和降解突变型SP-C的假设，防止细胞内蓄积、2型上皮细胞凋亡和进展为ILD。具体目标2将检验以下假设：叠加在Sftpc突变上的病毒感染导致细胞毒性SP-C和2型上皮细胞凋亡的积累，进而触发ILD发作或加速发病机制。具体目标3将检验抑制突变SP-C体内蓄积将防止进展为ILD的假设。本申请中提出的研究将产生家族性IPF的第一个小鼠模型，并确定疾病发作是否绝对需要环境损害;此外，该模型将允许测试体外研究结果的生物学相关性，特别是细胞毒性SP-C蓄积驱动进展为ILD的假设。小鼠模型也将促进翻译研究，其长期目标是（1）测试通过移植成体祖细胞逆转纤维化过程的可行性，（2）鉴定增强突变SP-C清除的新药（以及潜在的其他致病突变蛋白）并预防受影响小鼠的ILD，和（3）鉴定用于在无症状患者中早期检测疾病的候选基因。因此，本提案的总体长期目标是确定针对当前标准治疗为姑息治疗的疾病的新型诊断和治疗策略。公共卫生相关性：SFTPC基因座突变与家族性IPF之间的关联代表了一个真正独特的机会，可以生成具有未表征自然史的致死性疾病的动物模型。尽管SFTPC相关IPF是一种非常罕见的疾病亚组，但导致上皮细胞凋亡的分子途径可能与其他家族性疾病（例如，TERT或TR突变）共有，并且凋亡下游途径可能为非家族性特发性IPF提供信息。出于这个原因，我们提出了一个广泛的研究围绕Sftpc突变小鼠模型，这将有助于开发/识别新的疾病生物标志物，药物/药物靶点，和治疗。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with no effective treatment options and a mean survival of 3 years after diagnosis. The natural history of the disease is poorly understood because of the lack of an appropriate animal model. Familial forms of the disease account for less than 5% of total IPF cases and are characterized by autosomal dominant inheritance with variable penetrance related to the influence of both genetic modifiers and environmental factors. Mutations in the gene (SFTPC) encoding surfactant protein C (SP-C?exon4 and SP-CL188Q) provide a unique opportunity to identify molecular pathways underlying familial ILD. Our preliminary studies in cell culture have identified unique molecular complexes involved in the detection and rapid degradation of mutant SP-C; further, we have shown that cells expressing mutant SP-C and infected with respiratory syncticial virus accumulate misfolded SP-C and are much more susceptible to viral-induced cell death than cells expressing the wild type protein. These key in vitro findings lead to the central hypothesis that environmental stress superimposed on a SFTPC mutation leads to accumulation of misfolded, cytotoxic SP-C that, in turn, results in type 2 epithelial cell injury/death, which is the inciting event in SFTPC-associated familial ILD. Three specific aims are proposed to test this hypothesis: Specific Aim 1 will test the hypothesis that ERAD (a cytoprotective pathway) rapidly identifies and degrades mutant SP-C preventing intracellular accumulation, type 2 epithelial cell apoptosis, and progression to ILD. Specific Aim 2 will test the hypothesis that viral infection superimposed on an Sftpc mutation leads to accumulation of cytotoxic SP-C and type 2 epithelial cell apoptosis that, in turn, triggers the onset of ILD or accelerates pathogenesis. Specific Aim 3 will test the hypothesis that inhibiting accumulation of mutant SP-C in vivo will prevent progression to ILD. Studies proposed in this application will generate the first mouse model of familial IPF and determine if an environmental insult is absolutely required for onset of the disease; further, this model will permit testing of the biologic relevance of findings from in vitro studies, in particular the hypothesis that accumulation of cytotoxic SP-C drives progression to ILD. The mouse model will also facilitate translational studies with the long-term goals of (1) testing the feasibility of reversing the fibrogenic process by transplantation of adult progenitor cells, (2) identifying new drugs that enhance clearance of mutant SP-C (and, potentially, other disease-causing mutant proteins) and prevent ILD in affected mice, and (3) identifying candidate genes for early detection of disease in asymptomatic patients. Thus, the overall, long term-goal of this proposal is to identify novel diagnostic and treatment strategies for a disease in which the current standard of care is palliative. PUBLIC HEALTH RELEVANCE: The association between mutations in the SFTPC locus and familial IPF represents a truly unique opportunity to generate an animal model for a lethal disease with an uncharacterized natural history. Although SFTPC-associated IPF is a very rare disease subset, it is likely that the molecular pathways leading to epithelial cell apoptosis may be shared with other familial forms of the disease (e.g. mutations in TERT or TR) and pathways downstream of apoptosis may well be informative for non-familial, idiopathic IPF. For this reason, we have proposed a broad range of studies centered around an Sftpc mutant mouse model that will facilitate development/identification of novel disease biomarkers, drugs/drug targets, and therapies.