This renewal application proposes extensive studies focusing on the molecular genetics of the cutaneous basement membrane zone (BMZ) towards delineating the molecular defects in various forms of epidermolysis bullosa (EB). The proposed studies are designed to test the hypothesis that genes for structural macromolecules expressed at the BMZ cause one or more forms of EB. This application is based on solid progress during the past four years of research. The highlights of this progress include: (a) cloning of BMZ genes encoding human type VII collagen, bullous pemphigoid antigens 1 and 2, nidogen, and laminin A, B1 and B2 chain sequences; (b) chromosomal localization of 5 previously unassigned BMZ genes within the human genome; (c) demonstration of genetic linkage between the type VII collagen gene locus (COL7AI) and dominant dystrophic EB mutations in 4 families with defective anchoring fibrils; (d) genetic linkage of a family with dominant simplex EB to a locus on chromosome 12q adjacent to the type II keratin gene cluster, and mapping of another EB simplex family to a locus on chromosome 1q. The proposal for continuation of these studies entails concentrated, multi-disciplinary studies to be performed by investigators participating in the collaborative research within the Jefferson Institute of Molecular Medicine. The five component projects are highly interdependent. Project 1, """"""""Genetic Linkage Analysis of EB"""""""", is vital to rule in or rule out specific genes and alleles as candidates for mutation in families with EB. Project 2, """"""""Genetic Defects in BMZ Molecules"""""""", will provide precise information on the specific mutations in the gene-protein systems that are at fault in various forms of EB. Project 3, """""""" Transgenic Mice with EB"""""""", will introduce mutated BMZ gene sequences, which have been identified in Project 2, into transgenic mice, to examine the consequences of such mutations. Project 4, """"""""Biology of Type VII Collagen"""""""", will concentrate on elucidation of various aspects of cellular and molecular biology of type VII collagen towards identification of critical protein structures and elements regulating the expression of this gene. Project 5, """"""""Protein and Gene Structure for BMZ Components"""""""", will provide additional gene probes and information about the normal gene structures that are essential for studies in Projects 1, 2 and 3. These multidisciplinary studies are expected to provide precise information on the underlying molecular defects in various forms of EB. Such information is of critical importance in developing a definitive classification, for development of prenatal diagnostic tests, and to provide a basis for devising novel therapeutic approaches for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR038923-07
Application #
3092396
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1987-08-15
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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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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