This revised Mentored Career Development Award application (K01) revolves around pseudoxanthoma elasticum (PXE), a Mendelian autosomal recessive disorder characterized by ectopic mineralization of connective tissues in a variety of organs, including the skin, eyes, and the cardiovascular system, with considerable morbidity and mortality. PXE results from mutations in the ABCC6 gene which encodes a putative transmembrane transporter protein, ABCC6, which is expressed primarily in the liver, to a lesser extent in kidneys, and at very low levels, if at all, in tissues affected by PXE. Adding to the complexity of this disorder are the observations that there is considerable inter- and intra-familil heterogeneity. Genetic factors, environmental, and life style variables also modulate the progression and eventual outcome of the disease. This application will expand upon baseline skills of the applicant, Dr. Qiaoli Li, to address the overall goal of identifying and characterizig the major and minor modifier genes of ectopic cutaneous mineralization, a predominant feature of PXE, using mouse genetic approaches. Crossing the severely affected KK/HIJ mice with unaffected C57BL/6J mice which are wild type for the Abcc6 allelic mutation, and crossing the severely affected KK/HIJ mice with unaffected DBA/2J mice with the same Abcc6 allelic mutation as KK/HIJ mice, allows examination of their N2 progeny for Quantitative Trait Locus (QTL) analysis to identify modifier genes that potentially modifies the cutaneous mineralization phenotype. Functional in vivo characterization of the candidate genes will prove their importance in ectopic mineralization process. It is expected that the results of this study will provide novel insights into the molecular pathways leading to phenotypic variability in PXE, with relevance to common disorders involving ectopic mineralization. Understanding such pathways is expected to provide opportunities for the development of novel pharmacologic approaches to ameliorate, and perhaps cure, these currently intractable conditions. Having both Drs. Jouni Uitto and John P. Sundberg on the mentoring team provides Dr. Li with an outstanding opportunity to take advantage of their expertise, learn about their diverse skill sets, and to utilze resources they have accumulated. These provide resources to immediately utilize for these studies which will support the applicant's progress into becoming an independent researcher.

Public Health Relevance

This K01 proposal by a new investigator, Dr. Qiaoli Li, revolves around identification and characterization of major and minor modifier genes that regulate the phenotypic diversity and severity of pseudoxanthoma elasticum (PXE) using mouse models. PXE is a prototypic heritable skin disorder which is characterized by ectopic connective tissue mineralization. The information gleaned from this rare disorder will be applicable towards providing new diagnostic tools for subtyping patients with PXE, development of new therapeutic targets, and will help predict response to treatment. In broader sense, understanding the pathophysiology or molecular mechanisms underlying PXE, particularly the genetic modifiers of the phenotype at the genome- environment interface, may provide additional information on other relatively common disorders, such as arteriosclerotic vascular changes and calcinosis cutis associated with inflammatory skin diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Tseng, Hung H
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Thomas Jefferson University
Schools of Medicine
United States
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Zhang, Jieyu; Dyment, Nathaniel A; Rowe, David W et al. (2016) Ectopic mineralization of cartilage and collagen-rich tendons and ligaments in Enpp1asj-2J mice. Oncotarget 7:12000-9
Li, Qiaoli; Kingman, Joshua; Sundberg, John P et al. (2016) Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy. J Invest Dermatol 136:275-83
Li, Qiaoli; Arányi, Tamás; Váradi, András et al. (2016) Research Progress in Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders. J Invest Dermatol 136:550-6
Li, Qiaoli; Kingman, Joshua; Uitto, Jouni (2015) Mineral content of the maternal diet influences ectopic mineralization in offspring of Abcc6(-/-) mice. Cell Cycle 14:3184-9
Li, Qiaoli; Jin Chung, Hye; Ross, Nicholas et al. (2015) Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF-κB. J Invest Dermatol 135:1905-8
South, Andrew P; Li, Qiaoli; Uitto, Jouni (2015) Next-generation sequencing for mutation detection in heritable skin diseases: the paradigm of pseudoxanthoma elasticum. J Invest Dermatol 135:937-40
Li, Qiaoli; Sundberg, John P; Levine, Michael A et al. (2015) The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene. Cell Cycle 14:1082-9
Li, Qiaoli; Kingman, Joshua; Sundberg, John P et al. (2015) Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy. J Invest Dermatol :
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
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

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