Proteomics and Gene Expression in Hereditary Disorders of Connective Tissue

结缔组织的遗传性疾病，如Ehlers Danlos （EDS）、Loeys-Dietz、Marfan、Stickler、纤维肌肉发育不良（FMD）、血管性EDS （VEDS）和家族性动脉瘤综合征，在遗传和临床上都是异质性的。虽然许多致病基因是已知的，但还有许多是未知的。许多受影响的家庭成员可能有独特基因的突变，用通常的方法可能无法识别。

Hereditary disorders of connective tissue, such as Ehlers Danlos (EDS), Loeys-Dietz, Marfan, Stickler, Fibromuscular Dysplasia (FMD), Vascular EDS (VEDS), and Familial Aneurysm syndromes are genetically and clinically heterogeneous. While many of the causative genes are known, many others are not. Many affected family members may have mutations in unique genes that may be impractical to identify with usual methodologies. The goal of this project is to develop a comprehensive gene expression and a complementary protein profiling approach utilizing samples collected from affected patients through an IRB-approved protocol (2003-086). The hypothesis is that conditions that share a similar phenotype in terms of complications, regardless of the underlying gene mutation, the expression and proteomic profiles wil turn out to similar and amenable to treatment utilizing the same targets. For example, Loeys-Dietz syndrome is caused by mutations in TGFbetaR1&2, which are cell surface receptors, and Marfan syndrome is caused by mutations in FBN1, a structural extracellular matrix protein. Despite different causative mutations, both syndromes lead to derangements of the TGFbeta pathway, have phenotypic similarities, and are amenable to treatment by losartan, which is an angiotensin receptor blocker that is also a modulator of TGFbeta expression. We are utilizing whole genome expression arrays, RT-PCR 2-D protein electrophoresis, mass spectroscopy, western blot and immunochemistry approaches to investigate the consequences of known mutations in VEDS patients, and comparing the profiles of patients without such mutations but with similar phenotypic features, such as FMD. Recent results indicate that circulating TGFbeta1 levels are increased in patients with Marfan syndrome, VEDS, and FMD. The results of our findings in Marfan syndrome have been published and the other disorders are being prepared for publication. This is envisioned as a long term project given that more than 300 unique patient fibroblast lines from connective tissue patients are being studied in the lab.