This is a competing renewal application for a grant (R01 AR28450) which has been active since April 1981. The overall goal of this project, viz., definition of molecular defects in diseases affecting the extracellular matrix of connective tissues, remains the same. This proposal now focuses on pseudoxanthoma elasticum (PXE), a heritable disorder characterized by ectopic mineralization of elastic structures in the skin, the eyes, and the cardiovascular system, with considerable morbidity and mortality. Our research in the past, supported by this NIH grant, has led to identification of ABCC6 as the gene harboring mutations in PXE. We have developed an Abcc6-/- mouse model for PXE, and our recent studies have demonstrated that PXE is a metabolic disorder in which mutations in this gene expressed primarily in the liver result in ectopic mineralization of peripheral connective tissues. However, the precise function of ABCC6 in vivo, consequences of the corresponding gene mutations at the mRNA and protein levels, and the pathomechanistic details leading to mineralization of the elastic structures are currently unknown. In this application, we propose multi-disciplinary state-of-the-art approaches to dissect the pathomechanisms leading to PXE phenotype, based on the unifying hypothesis that PXE is a metabolic disorder at the genome-environment interface. The focus of this research is on the Abcc6-/- mouse which recapitulates genetic, histopathologic and ultrastructural features of PXE.
Specific Aim 1 proposes delineation of pathomechanisms of PXE, with emphasis on expansion of the ABCC6 mutation database and exploration of the genetic heterogeneity with respect to vitamin K-dependent genes GGCX and VKORC.
Specific Aim 2 focuses on identification of factors modifying the onset and phenotypic expression of PXE, both genetic and environmental.
Specific Aim 3 concentrates on development of molecular therapies for this, currently intractable, disease, utilizing information derived in this project from the Abcc6-/- mouse. We anticipate that these approaches will disclose the pathomechanistic details explaining the consequences of ABCC6 gene mutations at the phenotypic level, and provide the preclinical information serving as a critical platform for development of translational strategies to counteract this devastating multi-system disorder.

Public Health Relevance

This project, active since 1981, revolves around pseudoxanthoma elasticum (PXE), a heritable multisystem disorder with considerable morbidity and mortality. This proposal addresses the pathomechanistic features and phenotypic variability in PXE, with the overall goal to develop molecular therapies for this, currently intractable, disorder.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Tseng, Hung H
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Thomas Jefferson University
Schools of Medicine
United States
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Akoglu, Gulsen; Li, Qiaoli; Gokoz, Ozay et al. (2014) Clinical and histopathological characteristics of a family with R1141X mutation of pseudoxanthoma elasticum - presymptomatic testing and lack of carrier phenotypes. Int J Dermatol 53:692-8
Boraldi, Federica; Bartolomeo, Angelica; Li, Qiaoli et al. (2014) Changes in dermal fibroblasts from Abcc6(-/-) mice are present before and after the onset of ectopic tissue mineralization. J Invest Dermatol 134:1855-61
Li, Qiaoli; Chou, David W; Price, Thea P et al. (2014) Genetic modulation of nephrocalcinosis in mouse models of ectopic mineralization: the Abcc6(tm1Jfk) and Enpp1(asj) mutant mice. Lab Invest 94:623-32
Li, Qiaoli; Brodsky, Jill L; Conlin, Laura K et al. (2014) Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum. J Invest Dermatol 134:658-65
Li, Qiaoli; Jiang, Qiujie; Uitto, Jouni (2014) Ectopic mineralization disorders of the extracellular matrix of connective tissue: molecular genetics and pathomechanisms of aberrant calcification. Matrix Biol 33:23-8
Li, Qiaoli; Guo, Haitao; Chou, David W et al. (2014) Mouse models for pseudoxanthoma elasticum: genetic and dietary modulation of the ectopic mineralization phenotypes. PLoS One 9:e89268
Pomozi, Viola; Brampton, Christopher; Fulop, Krisztina et al. (2014) Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. J Invest Dermatol 134:946-53
Guo, Haitao; Li, Qiaoli; Chou, David W et al. (2013) Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6?/?). J Mol Med (Berl) 91:1177-84
Li, Q; Baker, J; Kowalczyk, J et al. (2013) Paediatric pseudoxanthoma elasticum with cardiovascular involvement. Br J Dermatol 169:1148-51
Li, Qiaoli; Guo, Haitao; Chou, David W et al. (2013) Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis Model Mech 6:1227-35

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