This second revision of a new grant application revolves around pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization of connective tissues in a variety of organs, including the skin, the eyes, and the cardiovascular system, with considerable morbidity and mortality. PXE is now known to result from mutations in the ABCC6 gene which encodes the multi-drug resistance-associated protein 6 (MRP6), a putative transmembrane transporter, expressed primarily in the liver, to a lesser extent in proximal tubules of kidneys, and at very low levels, if at all, in tissues afflicted by PXE. Adding to the complexity of this disorder are the observations that there is considerable both inter- and intra-familial heterogeneity, the diagnosis is often delayed due to late onset of manifestations, and a number of environmental and life-style variables appear to modulate the progression and eventual outcome of the disease. The pathomechanistic details leading from altered ABCC6 expression to aberrant mineralization in peripheral tissues are currently unknown. Specifically, the function of MRP6 and its physiologic ligand(s) remain undisclosed. This application will take advantage of the general progress made in understanding the ABC transporters and of our recent development of model systems to study this disorder. The application represents a consortium between three major research groups that will address the following Specific Aims: 1) The Abcc6-/- Mice as a Phenotypic Model of PXE;2) Characterization of Human ABCC6/MRP6 Transporter and Search for the Physiological Substrates.
The Specific Aim 1 proposes development of parabiosis and plasma/candidate protein supplementation, with extensive characterization of Abcc6-/- mice, as models for PXE.
The Specific Aim 2 proposes state-of-the-art technologies to identify physiologic substrate(s) for MRP6 with global and candidate molecule approaches. Such physiologic substrates will then be used for structure-function studies of MRP6.
These specific aims test the unifying hypothesis that PXE is a heritable disorder at the genome/environment interface, with an overall goal to define the molecular events that lead to phenotypic expression of PXE. The feasibility of this application is attested by our recent development of a mouse model for PXE through targeted ablation of the Abcc6 gene, and by establishment of the insect cell transport system to study the details of the MRP6 transport mechanisms as well as the effects of PXE mutations on it. It is expected that the results of this study will provide novel insights into the pathomechanistic pathways leading to aberrant mineralization in PXE and related heritable disorders, with perspective to common traits in general population, such as age-associated macular degeneration and arteriosclerosis. Understanding of such pathways is expected to provide opportunities for development of novel pharmacologic approaches to ameliorate, and perhaps cure, these currently intractable conditions. PUBLIC HEALTH REVELANCE. This research project revolves around pseudoxanthoma elasticum (PXE), a heritable disorder characterized by ectopic mineralization of connective tissues, with considerable morbidity and mortality. The overall goal of these studies is to identify the pathomechanistic pathways leading to abnormal mineralization, with translational implications. The results are expected to provide novel approaches to ameliorate, and perhaps cure, PXE and other related, currently intractable, mineralization disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Schools of Medicine
United States
Zip Code
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
Brampton, Christopher; Aherrahrou, Zouhair; Chen, Li-Hsieh et al. (2014) The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. Am J Pathol 184:159-70
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
Jansen, Robert S; Duijst, Suzanne; Mahakena, Sunny et al. (2014) ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol 34:1985-9
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
Uitto, Jouni; Jiang, Qiujie; Váradi, András et al. (2014) PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS. Expert Opin Orphan Drugs 2:567-577
Zhou, Yong; Jiang, Qiujie; Takahagi, Shunsuke et al. (2013) Premature termination codon read-through in the ABCC6 gene: potential treatment for pseudoxanthoma elasticum. J Invest Dermatol 133:2672-7
Berndt, Annerose; Li, Qiaoli; Potter, Christopher S et al. (2013) A single-nucleotide polymorphism in the Abcc6 gene associates with connective tissue mineralization in mice similar to targeted models for pseudoxanthoma elasticum. J Invest Dermatol 133:833-6
Li, Qiaoli; Guo, Haitao; Chou, David W et al. (2013) Warfarin accelerates ectopic mineralization in Abcc6(-/-) mice: clinical relevance to pseudoxanthoma elasticum. Am J Pathol 182:1139-50

Showing the most recent 10 out of 35 publications