This renewal application proposes extensive and innovative studies focusing on the molecular genetics of the cutaneous basement membrane zone (BMZ) towards delineating the molecular basis of various forms of epidermolysis bullosa (EB) and other selected genodermatoses affecting the epidermis. The proposed studies are designed to test the hypothesis that genetic lesions in structural genes expressed in the epidermis underlie variants of these diseases, and that the precise phenotype and mode of inheritance depend on the types and combinations of specific mutations in distinct genes. This application is based on solid progress in this project, including (a) expansion of the molecular basis of the recessive dystrophic forms of EB allowing refinement of genotype/phenotype correlations; (b) identification of novel and de novo COL7A1 mutations in dominant DEB, with an impact on genetic counseling of the families at risk of recurrence; (c) identification of a large number of novel and recurrent mutations both Herlitz and non-Herlitz junctional EB; (d) identification of uniparental disomy of chromosome 1 as a novel mechanism for H-JEB; (e) demonstration in mutations in the genes ITGA6 and ITGB4 encoding alpha-6-beta-4 integrins subunit polypeptides in EB with pyloric atresia,; (f) cloning of the human plectin gene and demonstration of mutations in EB with late-onset muscular dystrophy; (g) cloning of mouse type VII collagen and desmoglein 3 genes with development of """"""""knock-out"""""""" mice with blistering phenotype; (h) identification and characterization of several novel genes expressed into the epidermis, including periplakin, ladinin, and desmo-15; (i) refinement of RNA- DNA chimeric oligonucleotide technology for repair of the mutated genes in heritable skin diseases. This proposal details continuation of concentrated, multi-disciplinary studies in five highly interdependent projects: Project 1, """"""""Molecular Genetics of EB and Other Heritable Disorders of the Cutaneous BMZ and Epidermis,"""""""" will provide precise information on the specific mutations in the gene/protein system that are at fault in various forms of EB and other epidermal heritable disorders. Project 2, """"""""Identification and Characterization of Candidate Genes/Protein Systems Expressed in the Skin,"""""""" will provide new gene probes and information about novel genes as potential candidate genes for epidermal genodermatoses. Project 3, """"""""Consequences of the Mutations at the Protein Structure/Function Level"""""""" will examine the structural and functional alterations that result from distinct mutations in the candidate genes, utilizing computer modeling and monitoring functional interactions in biosensor analysis system. Project 4, """"""""Development and Testing of Animal Models for EB,"""""""" will generate novel animal models for EB. Project 5, """"""""Development of Non-Viral Gene Therapy for Cutaneous Diseases,"""""""" will concentrate on testing gene therapy approaches utilizing RNA/DNA chimeric oligonucleotide strategies. These multidisciplinary studies are expected to provide precise information of critical importance for translational applications towards development of refined classification, genotype/phenotype correlations, basis for genetic counseling, and prenatal testing, as well as providing the basis for novel gene therapy approaches for this devastating group of skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR038923-19
Application #
6863737
Study Section
Special Emphasis Panel (ZAR1-RJB-A (M2))
Program Officer
Baker, Carl
Project Start
1987-08-15
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
19
Fiscal Year
2005
Total Cost
$1,023,474
Indirect Cost
Name
Thomas Jefferson University
Department
Dermatology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Chung, Hye Jin; Uitto, Jouni (2010) Epidermolysis bullosa with pyloric atresia. Dermatol Clin 28:43-54
Chung, Hye Jin; Uitto, Jouni (2010) Type VII collagen: the anchoring fibril protein at fault in dystrophic epidermolysis bullosa. Dermatol Clin 28:93-105
Mahoney, My G; Sadowski, Sara; Brennan, Donna et al. (2010) Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol 130:968-78
Remington, Jennifer; Wang, Xinyi; Hou, Yingpin et al. (2009) Injection of recombinant human type VII collagen corrects the disease phenotype in a murine model of dystrophic epidermolysis bullosa. Mol Ther 17:26-33
Uitto, Jouni (2009) Progress in heritable skin diseases: translational implications of mutation analysis and prospects of molecular therapies*. Acta Derm Venereol 89:228-35
Lugassy, Jennie; McGrath, John A; Itin, Peter et al. (2008) KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol 128:1517-24
Igoucheva, Olga; Kelly, Aislinn; Uitto, Jouni et al. (2008) Protein therapeutics for junctional epidermolysis bullosa: incorporation of recombinant beta3 chain into laminin 332 in beta3-/- keratinocytes in vitro. J Invest Dermatol 128:1476-86
Nakajima, Koji; Tamai, Katsuto; Yamazaki, Takehiko et al. (2008) Identification of Skn-1n, a splice variant induced by high calcium concentration and specifically expressed in normal human keratinocytes. J Invest Dermatol 128:1336-9
Varki, Roslyn; Sadowski, Sara; Uitto, Jouni et al. (2007) Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet 44:181-92
Nyquist, Gurston G; Mumm, Christina; Grau, Renee et al. (2007) Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients. Am J Med Genet A 143:734-41

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