The candidate, Lawrence S. Chan, is an Assistant Professor of Dermatology at the Northwestern University Medical School. After graduating form the University of Pennsylvania School of Medicine in 1985, Dr. Chen obtained his Dermatology residency training at the University of Michigan Medical School under the leadership of Dr. John J. Voorhees. He was also trained as an Immunodermatology fellow at the same institution under the mentorship of Dr. Kevin D. Coper, a cellular immunologist, and Dr. James T Eler, a molecular biologist. The candidate's career interest is in the area of human autoimmunity against skin basement membrane zone (BMZ) components. During his residency, Dr. Chan discovered a new immunemediated blistering skin disease characterized by autoantibodies against a 105-kDa BMZ component at the lower lamina lucida. The candidate's short-term goals are to purify this new BMZ component and clone the human gene encoding for this new component. The candidate's long-term goals are to understand the functions of this new BMZ component: its relationship to other BMZ components, its influence on epidermal cell biology, its antigenic domains, and its pathophysiologic role in inducing autoimmune reaction. The research specific aims for the next five years, are to purify this 105- kD component, to isolate the human cDNA that encodes for this component, and to determine its functional domains. To achieve these specific aims, fibroblast protein will be subjected to multiple chromatographic columns, including Mono Q anion-exchange and reverse phase columns, for purification. The purified fractions will be analyzed by 2-dimensional gel electrophoresis and immunoblotting. The internal amino acid sequences will be obtained after proteolytic digestion of th purified protein. Monoclonal antibodies raised against the 105-kDa component and polyclonal antibodies raised against the amino-terminal peptide will be utilized to screen a human fibroblast cDNA expression library. Positive plaques will be subjected to cloning and DNA sequencing. Once the entire cDNA is delineated, multiple fusion proteins will be generated to examine the antigenic domains, the cellular and extracellular attachment domains, and the domains that influence keratinocyte biology. Understanding the structure and function of this new lamina lucida component will shed light on our understanding of the complex structure of the skin BMZ, the relationship between different components of skin BMZ, and their roles in epidermal-dermal adhesion, human blistering diseases, gestational development, and wound healing. The research environment provided for Dr. Chan at the northwestern University include; a Biotechnology Core Facility for protein microsequencing, peptide and oligonucleotide synthesis, monoclonal antibody production, two-dimensional gel electrophoresis, flow cytometry, molecular biology supplies, and an Animal Care Facility, all in the same research building as Dr. Chan's laboratory. The Department of Dermatology has several faculty members who can assist Dr. Nageswararao, another collaborator, is a protein biochemist, Dr. Woodley, the candidate's primary sponsor, is a protein biochemist and is well acquainted with epithelial cell biology. The Department of Dermatology has a departmental library which contains many major scientific journals and a state-of-the-art Fast Protein Liquid Chromatography system that can facilitate Dr. Chan's protein purification. Dr. Chan has been provided a fully equipped 660 square-feet laboratory space, a 200 square-feet office space adjacent to his laboratory, a culture room, and an electron microscope. In addition, the candidate has 80% projective time devoted to research. Together, this environment provides sufficient support for the candidate to succeed in his research effort.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Northwestern University at Chicago
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United States
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Jean-Baptiste, S; O'Toole, E A; Chen, M et al. (2002) Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol 127:470-8
Xu, L; Robinson, N; Miller, S D et al. (2001) Characterization of BALB/c mice B lymphocyte autoimmune responses to skin basement membrane component type XVII collagen, the target antigen of autoimmune skin disease bullous pemphigoid. Immunol Lett 77:105-11
Schachter, M; Brieva, J C; Jones, J C et al. (2001) Pemphigoid nodularis associated with autoantibodies to the NC16A domain of BP180 and a hyperproliferative integrin profile. J Am Acad Dermatol 45:747-54
Chan, L S; Robinson, N; Xu, L (2001) Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol 117:977-83
Olivry, T; Dunston, S M; Schachter, M et al. (2001) A spontaneous canine model of mucous membrane (cicatricial) pemphigoid, an autoimmune blistering disease affecting mucosae and mucocutaneous junctions. J Autoimmun 16:411-21
Olivry, T; Mirsky, M L; Singleton, W et al. (2000) A spontaneously arising porcine model of bullous pemphigoid. Arch Dermatol Res 292:37-45
Xu, L; O'Toole, E A; Olivry, T et al. (2000) Molecular cloning of canine bullous pemphigoid antigen 2 cDNA and immunomapping of NC16A domain by canine bullous pemphigoid autoantibodies. Biochim Biophys Acta 1500:97-107
Gandhi, K; Chen, M; Aasi, S et al. (2000) Autoantibodies to type VII collagen have heterogeneous subclass and light chain compositions and their complement-activating capacities do not correlate with the inflammatory clinical phenotype. J Clin Immunol 20:416-23
O'Toole, E A; Mak, L L; Guitart, J et al. (2000) Induction of keratinocyte IL-8 expression and secretion by IgG autoantibodies as a novel mechanism of epidermal neutrophil recruitment in a pemphigus variant. Clin Exp Immunol 119:217-24
Olivry, T; Borrillo, A K; Xu, L et al. (2000) Equine bullous pemphigoid IgG autoantibodies target linear epitopes in the NC16A ectodomain of collagen XVII (BP180, BPAG2). Vet Immunol Immunopathol 73:45-52

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