Director, UC Denver Skin Disease Research Core
University of Colorado Denver
Autoimmune skin diseases (vitiligo, alopecia areata http://www.alopeciaareata.com/research/research-registry.asp
lupus erythematosus), immunobullus diseases, psoriasis, acne,
skin cancer, melanoma and cutaneous lymphoma, pigmentary disorders.
Cytotoxic Mechanism in Cutaneous Disease:
A comprehensive study of the defense mechanisms that protect epidermal melanocytes and keratinocytes from immunologic cytotoxicity, especially the induction of apoptosis.
1: To confirm that bcl-2 is a major anti-apoptotic defense in melanocytes and melanoma cell lines, and to demonstrate that the high levels of bcl-2 in these cells depend on activation of the ras signalling pathway by integrin or neurotrophin receptor ligation. High bcl-2 expression will be shown to render melanocytes and melanoma cells resistant to immunologic cytotoxicity.
2: To verify that keratinocyte resistance to apoptosis can also be modulated by activation of ras signalling pathways by integrins or neurotrophin receptors. To demonstrate that susceptibility of keratinocytes to immunologic cytotoxicity will be modulated byras activation or inactivation.
3: To determine whether p53 activation decreases anti-apoptotic defenses in keratinocytes in the same way that it does in melanocytes/melanomas.
Melanoma Resistance to Apoptosis:
A comprehensive study of the anti-apoptotic defenses of melanoma , and ways to reverse these defenses.
1: To determine whether activated ras increases cell resistance to apoptotic triggers, especially anti-cancer chemotherapy agents.
2: To investigate the mechanisms and signaling pathway(s) by which activated ras increases survival of melanomas and enhances resistance to chemotherapy. a) Whether activated ras regulates control and "program" parts of apoptosis. b) Whether the signaling pathway is via MAPK (mitogen-activated-protein kinase) cascade and CREB (Cyclic AMP responsive element binding protein).
3: To investigate whether blocking activity of signaling pathway from Ras, CREB, to Bcl-2 decreases cell survival of these melanoma cell lines, which would test whether the involvement of these proteins are specific, and might lead to improved cancer therapies.
Control of Migration in Melanoma:
This is a collaborate laboratory/clinical program with Dr. Karl Pfenninger to determine the factors that control melanoma migration, and changes in melanoma migration with progression.
1: To define the elements of the phospholipase A2, lipoxygenase, Protein Kinase C, and MARCKS (PLPM) Pathway in melanomas at different stages of progression.
2: To determine the effect of progression mutations and cellular repellents on controlling melanoma dispersal and invasion from dermal tumors.
3: to disrupt the PLPM pathway by transfection of key componentns on the pathway and determine the effect on melanoma progression.
Resistance to Activation Induced Cell Death in Cutaneous T cell Lymphoma:
This is a collaborative project with Drs. Sandy Meech, Patrick Walsh and Richard Duke to define the resistance of CTCL to activation induced cell death.
1: To define the deficiencies in Fas-mediated cell death in malignant circulating lymphocytes in the Sezary Syndrome
2: To develop biochemical approaches to reverse this resistance
3: To develop clinical trials using the agents identified in aim 2.
Role of Bacterial Toxins in Human Skin Diseases:
This is a collaborative project with Dr. Donald Leung to study of the role of bacterial superantigens in inducing and modulating cutaneous inflammation in atopic dermatitis and psoriasis.
1: To deterime whether atopic dermatitis and psoriasis is associated with a selective expansion of I cells expressing a particular VB gene segment.
2: To determine the clonality of T cells expressed in atopic dermatitis and psoriasis.
3: To investigate the role of bacterial toxins in atopic dermatitis and psoriasis.