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CELL DEATH IN NORMAL AND DISEASED HUMAN EPIDERMIS

Award Number: R01AR047814
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 06/01/2002
PERIOD OF PERFORMANCE END DATE: 05/31/2007

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CELL DEATH IN NORMAL AND DISEASED HUMAN EPIDERMIS - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $291,032 )
2006	2006	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/1/2006	NON-COMPETING CONTINUATION	$291,032
														Subtotal = $291,032

Issue Date FY: 2005 ( Subtotal = $298,035 )
2005	2005	LOYOLA UNIVERSITY MEDICAL CENTER							Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/10/2005	NON-COMPETING CONTINUATION	$298,035
														Subtotal = $298,035

Issue Date FY: 2004 ( Subtotal = $323,010 )
2004	2004	LOYOLA UNIVERSITY MEDICAL CENTER							Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/1/2004	NON-COMPETING CONTINUATION	$323,010
														Subtotal = $323,010

Issue Date FY: 2003 ( Subtotal = $323,010 )
2003	2003	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/30/2003	NON-COMPETING CONTINUATION	$323,010
														Subtotal = $323,010

Issue Date FY: 2002 ( Subtotal = $323,010 )
2002	2002	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/1/2002	NEW	$323,010
														Subtotal = $323,010

Grand Total All Awards = $1,558,097

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CELL DEATH IN NORMAL AND DISEASED HUMAN EPIDERMIS

Award Number: R01AR047814

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 06/01/2002

PERIOD OF PERFORMANCE END DATE: 05/31/2007

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