The epidermal compartment of human skin is strategically located at the interface with the environment, shielding the body from harmful physical, chemical, and infectious agents that could perturb homeostasis. The epidermis creates this barrier, or surface seal, by production of a stratum corneum formed by keratinocytes (KCs) that have undergone terminal differentiation and cell death. Not only must proper regulation of cell death balance cell proliferation to maintain a consistent and physiologically acceptable thickness of epidermis, the molecular events that orchestrate cell death must also be properly timed to occur in both a spatially and temporally coordinated fashion to produce an effective barrier. This orderly epidermal process has been termed """"""""planned cell death"""""""", and the molecular events that regulate epidermal cell death are the focus of this proposal. Our hypothesis is that a distinct set of biochemical reactions underlie this vital apoptotic process, involving a variety of key molecular participants including: specific death receptors that primarily belong to the tumor necrosis family, as well as decoy receptors, death ligands, caspase cascades, and transcription factors. We propose to perform a systematic and comprehensive series of experiments to initially define this planned cell death pathway in normal human skin, and then utilizing this new knowledge to investigate several skin disorders that feature either dysregulated and/or premature KC cell death. Preliminary evidence indicates distinctive molecular changes related to the biochemical apoptotic machinery can be localized to specific layers of epidermis, and that specific death pathways are also abnormal in the aforementioned skin diseases. Moreover, a growing body of evidence highlights our experimental design, as it is becoming clear that a full explanation for cell death in the epidermis needs to be approached as a problem in cell biology as well as one in biochemistry. This grant features a transition of experimental protocols beginning with conventional tissue culture techniques, and then moving to the use of living epidermal equivalents that contain stratified layers of KCs that can be triggered to undergo terminal differentiation and cornification by lifting the culture to an air/liquid interface. Utilizing these ex-vivo epidermal equivalents will facilitate dissection of molecular events that produce terminal differentiation/cornification. By successfully completing the proposed objectives, therapeutic strategies will emerge that are important to develop new and improved methods that may be useful in a variety of clinical settings including: accelerating barrier function formation; preventing premature apoptosis; reducing or delaying the onset of skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047814-05
Application #
7077799
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Baker, Carl
Project Start
2002-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
5
Fiscal Year
2006
Total Cost
$291,032
Indirect Cost
Name
Loyola University Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Chaturvedi, Vijaya; Bodner, Barbara; Qin, Jian-Zhong et al. (2006) Knock down of p53 levels in human keratinocytes increases susceptibility to type I and type II interferon-induced apoptosis mediated by a TRAIL dependent pathway. J Dermatol Sci 41:31-41
Perera, Ranjan J; Koo, Seongjoon; Bennett, C Frank et al. (2006) Defining the transcriptome of accelerated and replicatively senescent keratinocytes reveals links to differentiation, interferon signaling, and Notch related pathways. J Cell Biochem 98:394-408
Chaturvedi, Vijaya; Sitailo, Leonid A; Bodner, Barbara et al. (2006) Defining the caspase-containing apoptotic machinery contributing to cornification in human epidermal equivalents. Exp Dermatol 15:14-22
D'Costa, A M; Robinson, J K; Maududi, T et al. (2006) The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas. Oncogene 25:378-86
Bacon, Patricia; Bodner, Barbara; Nickoloff, Brian J (2005) Senescent human keratinocytes suppress colony formation of HeLa cells. J Dermatol Sci 38:64-6
Quinn, Adam M; Brown, Kimberly; Bonish, Brian K et al. (2005) Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis. Arch Dermatol 141:683-7
Chaturvedi, Vijaya; Sitailo, Leonid A; Qin, Jian-Zhong et al. (2005) Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-x(L) reduction thereby enhancing UV-light induced apoptosis. Oncogene 24:5299-312
Nickoloff, Brian J; Ben-Neriah, Yinon; Pikarsky, Eli (2005) Inflammation and cancer: is the link as simple as we think? J Invest Dermatol 124:x-xiv
Qin, Jian-Zhong; Bacon, Patricia; Panella, Jeffrey et al. (2004) Low-dose UV-radiation sensitizes keratinocytes to TRAIL-induced apoptosis. J Cell Physiol 200:155-66
Nickoloff, Brian J; Lingen, Mark W; Chang, Bey-Dih et al. (2004) Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. Cancer Res 64:2956-61

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