Today is Wednesday, Dec. 13, 2017

Department of

Dermatology

Basic Research 

 

Zalfa Abdel-Malek, PhD, Research Laboratory

Zalfa Abdel-Malek, PhD

The Abdel-Malek laboratory is best known for its contributions to the understanding of the regulation of human pigmentation and the response of human melanocytes to ultraviolet radiation (UVR), the major causative factor for skin cancers including melanoma.

Dr. Abdel-Malek has pioneered the research on the significance of melanocortins and the melanocortin 1 receptor (MC1R) in regulating human melanocytes. She first demonstrated that activation of the human MC1R, a Gs protein-coupled receptor that is expressed on the cell surface of melanocytes, by its agonists α-melanocortin (α-MSH) and adrenocorticotropic hormone (ACTH), stimulates the synthesis of the dark pigment eumelanin, as well as proliferation.

She subsequently made the seminal discovery that the MC1R activates DNA repair pathways and reduces oxidative stress in melanocytes exposed to UVR.

The MC1R gene is highly polymorphic, and some of its allelic variants are strongly associated with red hair phenotype and increased melanoma risk. She has been interested in elucidating the impact of various MC1R genotypes on the function of the receptor and the response of melanocytes to UVR.

This led to establishing a panel of human melanocyte cultures that are well-characterized for their MC1R genotype, pigmentary status, and response to melanocortins and UVR. She found that melanocytes homozygous or compound heterozygous for two red hair allelic variants express loss-of-function MC1R, and thus have compromised DNA repair and antioxidant capacities.

These findings offer an explanation for the role of the MC1R as a melanoma susceptibility gene.

From Bench to the Bedside
Our studies on the MC1R have led Dr. Abdel-Malek to start moving her basic science findings from the bench to the bedside.

In collaboration with medicinal chemists at the University of Cincinnati and other institutions, she developed small peptide analogs of α-MSH, tetrapeptides that were more potent than α-MSH, and tripeptides that retained considerable ability to activate the MC1R, for the goal of utilizing them as topical agents for melanoma prevention.

These analogs mimicked α-MSH in all its effects on melanocytes. In an ongoing preclinical trial, she is testing the effects of topical application of our analogs on repair of UVR-induced DNA damage and the onset of melanoma tumors in mouse melanoma models.

Research Collaboration
The Abdel-Malek research program has been enriched by collaboration with leaders in the fields of pigment and melanoma research. Her laboratory has been the site of training for numerous visiting scientists from various countries, postdoctoral fellows, medical and graduate students.

 

 

Raymond Boissy, PhD, Research Laboratory

Raymond Boissy, PhD

The overall theme of the research in Dr. Boissy’s laboratory is twofold - 1. To analyze the molecular and cellular mechanism responsible for trafficking gene products from their site of synthesis to their site of action during organelle biosynthesis using the melanocytes as a model system, and 2. Understand the pathological processes underlying various pigmentary diseases (e.g., albinism, vitiligo, melasma, post-inflammatory pigmentation etc.).

 

Current specific projects include:

  • Hermansky-Pudlak Syndrome (HPS)
    Hermansky-Pudlak Syndrome (HPS) is a congenital, potentially fatal, multi-system disorder presenting with oculocutaneous albinism, a mild to severe bleeding diathesis and ceroid storage disease. These characteristics result from aberrations in a specific group of cellular organelles, (e.g., the pigment granules of the melanocyte, the dense bodies of the platelet, and the lysosome/residual body of the reticular cell respectively).

    To date, six genes, HPS1, ADTB3A, and HPS3-6 are associated with HPS. While ADTB3A codes for the b3A subunit of adaptor complex-3, the functions of the HPS, and 3-6 gene products remain unknown. It is hypothesized that the genes affected in HPS putatively regulate specific molecular steps in the trafficking of Golgi derived cargo proteins to a target organelle common in the cell types affected. We are currently characterizing the role of HPS in the regulation of this cellular pathway. (This research is funded by the National Institutes of Health.)

  • Vitiligo
    Vitiligo is an acquired cutaneous disease in which the melanocyte component of the skin is destroyed, resulting in amelanotic lesions of variable size and extent. As a health consequence, the white lesions of the skin become immunocompromised and also become susceptible to cancer.

    The etiology of vitiligo consists of multiple factors including genetic, cytotoxic and autoimmune components. The current prevailing hypothesis is that some inducing agent triggers the genetically susceptible “vitiligo” melanocytes into an autolytic process. 

    Subsequently, an autoimmune response develops in the patient that appears to exacerbate the disease. We are currently characterizing the etiology of this disease that affects 1 percent of the human population worldwide. (This research is funded by NIH and the National Vitiligo Foundation.)

  • Skin Complexion Color
    Skin complexion color is important to one’s self-image and is considered an indicator of physical health. Complex determinants are involved human skin pigmentation. In this respect, epidermal melanocytes synthesize pigmented melanosomes that are eventually transferred to and retained by keratinocytes.

    The resulting skin color is determined by a combination of the extent of pigment production by melanocytes and the efficiency of receipt and processing of melanosomes by keratinocytes.

    The former process has been thoroughly investigated, defining the role of major enzymes in the melanization pathway. In contrast, little is known about intercellular melanosome transfer. We are currently characterizing the molecular mechanism regulating this unique transfer process.  (This research is funded by industry.)

 

 

Ana Luisa Kadekaro, PhD, Research Laboratory

Ana Luisa Kadekaro, PhD

Dr. Kadekaro’s laboratory investigates the biology of human melanocytes, particularly in response to UV radiation. Her laboratory has the expertise and techniques for mechanisms that activate the complex antioxidant network of melanocytes in response to ultraviolet radiation.

The long-term goals of her research include identifying the paracrine factors essential for maintenance of skin homeostasis, particularly after solar exposure.

The understanding of the signaling pathways, their cross-talk and conversation points in response to major environmental insults is a vast and promising area of research for the identification of new molecular targets for skin cancer prevention. 

Ana Luisa Kadekaro, PhD, with Zalfa Abdel-Malek, PhD

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