- In three specific aims the applicant will study the biology and pathology of the elastic fiber system. In the first aim the applicant will investigate the regulation of the elastin gene expression in cultured cells and transgenic mice with emphasis on the role of cis elements and transacting factors critical for transcriptional regulation of the human elastin promoter. These studies will concentrate on TGF-beta and UV irradiation.
The second aim will explore the molecular interactions of the elastic fiber network proteins necessary for elastin fibrillogenesis. These studies will utilize the yeast two-hybrid system to identify proteins binding to elastin and big-h3, a microfibrillar protein, by utilizing constructs with cloned human cDNAs in the two-hybrid binding domain. The interacting clones will be characterized, and the physiological relevance of the interactions will be confirmed by immunoprecipitation and protein overly assays. These studies are expected to provide critical information of the molecular interactions necessary for proper assembly of the elastic fibers during development, growth, and repair. In the third aim the applicant will search for mutations that cause pseudoxanthoma elasticum (PXE), a multisystem heritable disorder affecting skin, eyes, and the cardiovascular system. They will concentrate on candidate genes in an approximately 500kb locus identified by an international consortium on chromosome 16p13.1. The applicant expects these approaches will allow specific defects in the genes involved in elastin fibrillogenesis to be described. Collectively the applicant expects the proposed studies will have major implications towards understanding the factors regulating the expression of the elastin gene, assembly of the elastic fibers in normal cells and tissues, and their alterations in diseases with aberrant elastic fibers.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Moshell, Alan N
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Thomas Jefferson University
Schools of Medicine
United States
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Li, Qiaoli; Kingman, Joshua; van de Wetering, Koen et al. (2017) Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum. J Invest Dermatol 137:1025-1032
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 136:275-283
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
Jin, Liang; Jiang, Qiujie; Wu, Zhengsheng et al. (2015) Genetic heterogeneity of pseudoxanthoma elasticum: the Chinese signature profile of ABCC6 and ENPP1 mutations. J Invest Dermatol 135:1294-1302
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; Price, Thea P; Sundberg, John P et al. (2014) Juxta-articular joint-capsule mineralization in CD73 deficient mice: similarities to patients with NT5E mutations. Cell Cycle 13:2609-15
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
Li, Qiaoli; Pratt, C Herbert; Dionne, Louise A et al. (2014) Spontaneous asj-2J mutant mouse as a model for generalized arterial calcification of infancy: a large deletion/insertion mutation in the Enpp1 gene. PLoS One 9:e113542
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 134:1855-1861
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 134:658-665

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