The NIH K23 mentored award provides the necessary foundation for me to fulfill my career goals of being an independently-funded clinical investigator focusing on the gene and immunologic profiles of cutaneous lupus erythematosus (CLE) patients and becoming an expert in forecasting systemic involvement in CLE patients. The mentored award will also help me achieve my immediate goals of obtaining expertise in microarrays and skin immunology, and establishing a disease registry. Under the auspices of the University of Texas Southwestern (UTSW) Medical Center, I hope to attain these objectives through: 1) mentorship from a group of nationally recognized physicians who are experts in microarrays and skin immunology, and have established disease registries, and 2) classroom education and research resources afforded through the NIH Clinical and Translational Science Award at UTSW. My mentored research project centers on discoid lupus erythematosus (DLE), a disease whose etiology is not well understood. Because of its association with systemic lupus erythematosus (SLE), discoid skin lesions represent an untapped, yet easily accessible resource that could bear great relevance to SLE pathogenesis. This project seeks to identify genes distinctive to DLE (Aim 1), proteins highly expressed by DLE skin resident T cells (Aim 2), and genes linked to systemic spread in DLE subjects (Aim 3).
Aim 1 compares gene expression profiles of the skin of DLE subjects without SLE (DLE-only) and normal controls to better define DLE. We will perform microarray analyses on active discoid lesional skin and age-, gender-, and site-matched normal skin. We predict that DLE- only skin will up-regulate type I interferon-regulated and cell-mediated immunity genes versus normal skin.
Aim 2 centers on protein expression of skin resident T cells, which dominate the inflammatory cell infiltrate in discoid lesions. We will isolate these T cells from DLE-only and normal skin biopsies placed on top of tantalum- coated carbon matrices and perform flow cytometry analyses to compare T cell surface protein (Study 2a) and intracellular cytokine and cytotoxic protein expression (Study 2b). We postulate that compared with their normal counterparts, DLE-only skin resident T cells will have higher expression of cell surface, cytokine, and cytotoxic proteins associated with TH1 and CD8+ T cells.
Aim 3 will contrast gene profiles in DLE subjects with SLE (DLE+SLE) and DLE-only subjects to identify genes associated with systemic spread in DLE. We will perform microarray analyses on active lesional skin (Study 3a) and peripheral blood mononuclear cells (Study 3b) from both groups. We hypothesize that DLE+SLE subjects will up-regulate expression of genes regulated by tumor necrosis factor receptor, nuclear factor-?B, and PI3K/AKT/mTOR pathways compared with DLE-only subjects. Identification of genes and proteins up-regulated in DLE skin and DLE skin resident T cells, respectively, will provide greater clarity to disease pathogenesis. Moreover, knowledge of genes associated with systemic involvement in DLE subjects will enhance understanding of disease course.

Public Health Relevance

This project seeks to identify distinctive genes in the skin of discoid lupus erythematosus (DLE) patients, study protein expression in T cells residing in DLE skin, and pinpoint genes connected to systemic disease involvement in DLE patients. The information gained from this project will further elucidate the pathogenesis of and disease progression in DLE and produce novel therapeutic targets for DLE and SLE patients. Furthermore, this data could augment current diagnostic methods and treatment plans for DLE patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR061441-02
Application #
8500214
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Wang, Yan Z
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$123,012
Indirect Cost
$9,112
Name
University of Texas Sw Medical Center Dallas
Department
Dermatology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Kim, Andrew; O'Brien, Jack; Tseng, Lin-Chiang et al. (2014) Autoantibodies and disease activity in patients with discoid lupus erythematosus. JAMA Dermatol 150:651-4
Jost, Sheridan A; Tseng, Lin-Chiang; Matthews, Loderick A et al. (2014) IgG, IgM, and IgA antinuclear antibodies in discoid and systemic lupus erythematosus patients. ScientificWorldJournal 2014:171028
Thorpe, Ryan B; Gray, Anna; Kumar, Kirthi R et al. (2014) Site-specific analysis of inflammatory markers in discoid lupus erythematosus skin. ScientificWorldJournal 2014:925805
Chong, Benjamin F; Tseng, Lin-Chiang; Kim, Andrew et al. (2014) Differential expression of BAFF and its receptors in discoid lupus erythematosus patients. J Dermatol Sci 73:216-24
Kim, Andrew; Chong, Benjamin F (2013) Photosensitivity in cutaneous lupus erythematosus. Photodermatol Photoimmunol Photomed 29:4-11
Yang, Shirley Y; Bernstein, Ira; Lin, Danielle Q et al. (2013) Photoprotective habits of patients with cutaneous lupus erythematosus. J Am Acad Dermatol 68:944-51