Defective c-MET signaling in African American scleroderma patients

非裔美国硬皮病患者的 c-MET 信号传导缺陷

• 批准号: 8295198
• 负责人: RICHARD M. SILVER
• 金额: $ 31.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295198
• 关键词: Accounting; Address; African American; Age; American; Biological Markers; Bronchoalveolar Lavage; Chest; Code; Collaborations; Complication; DNA; Defect; Dermal; Development; Diagnostic; Disease; Disease Outcome; Dyspnea; Exhibits; Extracellular Matrix Proteins; Fibroblasts; Gender; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hepatocyte Growth Factor; High Resolution Computed Tomography; Instruction; Interstitial Lung Diseases; Knowledge; Lead; Leukocytes; Link; Lung; Lung diseases; MET gene; Methodology; Molecular; Morbidity - disease rate; Mutation; Patients; Phosphorylation; Prevalence; Proteins; Proto-Oncogene Protein c-met; Pulmonary function tests; Punch Biopsy; Race; Recombinants; Regulation; Research; Resources; Rheumatism; Scleroderma; Severities; Severity of illness; Signal Pathway; Signal Transduction; Skin; Somatic Mutation; Source; Systemic Scleroderma; Testing; Variant; genetic analysis; genetic variant; health disparity; indexing; meetings; mortality; mutant; peripheral blood; prognostic; racial difference; success

PROJECT SUMMARY (See instructions): Interstitial lung disease (ILD) is a major complication and the leading cause of mortality in scleroderma (SSc, systemic sclerosis). The morbidity and mortality rates in African American scleroderma patients are higher when compared with SSc patients of other races. The goal of this project is to fill gaps in knowledge of pathophysiologic links between African American race and SSc-ILD that may account for the racial differences in SSc-ILD outcomes, and potentially other rheumatic lung disease outcomes as well. In studies to date we identified a genetic variant in African American SSc patients that is likely to be responsible for the higher severity of SSc-ILD in African-Americans. In particular, we found that hepatocyte growth factor (HGF) receptor c-MET in lung fibroblasts from African American SSc-ILD patients contains the mutation D1398G that is not observed in white patients. Moreover, in cultured SSc lung fibroblasts from whites HGF downregulates the expression of extracellular matrix (ECM) proteins, whereas in fibroblasts from the African American SSc patients who have mutation D1398G, HGF does not exhibit this activity due to its inability to induce c-MET phosphorylation. Thus, our results suggest that the defective phosphorylation of HGF receptor in African American SSc lung fibroblasts is a direct consequence of the D1398G mutation. Our organizing hypotheses that drive this component project of the MCRC are that severity of SSc-ILD in African American patients is caused by a defect in the phosphorylation mechanisms of c-MET regulation of ECM proteins in lung, and that the D1398G variant of the c-MET gene is the source of this defect. Specific Aim 1 will test the hypothesis that D1398G variant of c-MET gene is a somatic mutation that modulates the disease severity in SSc-ILD patients. Specific Aim 2 will test the hypothesis that specific SNPs within the coding region of c-MET gene will be associated with D1398G variant of c-MET in SSc-ILD patients, thereby leading to a potential biomarker of SSc-ILD severity. Specific Aim 3 will test the hypothesis that D1398G variant of c-MET gene is causally responsible for the defective HGF signaling in African American SSc patients. The combined results of these studies will enhance our understanding of the molecular mechanisms of SSc-ILD and ultimately may lead to the development of effective diagnostics, prognostics and therapies that will depend on and can be tailored to the patient s genotype.

项目总结(见说明)： 间质性肺病(ILD)是硬皮病(SSC，全身性硬化症)的主要并发症和主要死亡原因。非裔美国人硬皮病患者的发病率和死亡率高于其他种族的硬皮病患者。该项目的目标是填补非裔美国人种族和SSc-ILD之间的病理生理联系的知识空白，这种联系可能解释SSC-ILD结果的种族差异，以及潜在的其他风湿性肺部疾病结果。在研究中 到目前为止，我们在非裔美国人SSC患者中发现了一种基因变异，这可能是非裔美国人SSC-ILD严重程度较高的原因。特别是，我们发现非裔美国人SSC-ILD患者肺成纤维细胞中的肝细胞生长因子(HGF)受体c-met含有D1398G突变，这在白人患者中没有观察到。此外，在培养的白人SSC肺成纤维细胞中，HGF下调细胞外基质(ECM)蛋白的表达，而在非洲人成纤维细胞中 突变为D1398G，HGF的美国SSC患者由于不能诱导c-met磷酸化而没有表现出这种活性。因此，我们的结果表明，非裔美国人SSC肺成纤维细胞中HGF受体的磷酸化缺陷是D1398G突变的直接结果。我们的组织假说推动了MCRC的这个组成部分项目，即非裔美国人SSC-ILD的严重程度是由c-met调节的磷酸化机制缺陷引起的。 C-met基因的D1398G变异是这一缺陷的来源。 具体目的1将验证c-met基因D1398G变异是调节SSC-ILD患者疾病严重程度的体细胞突变的假设。SSC-ILD患者c-Met基因编码区的特定SNPs与c-Met的D1398G变异相关，从而成为SSC-ILD严重程度的潜在生物标记物。具体目标3将验证c-met基因D1398G变异与非裔美国人SSC患者HGF信号缺陷的因果关系的假设。这些研究的综合结果将加深我们对 SSc-ILD的分子机制，并最终可能导致有效的诊断、预后和治疗方法的发展，这些将依赖于并可以根据患者S的基因定制。