HUSCRI uses its dedicated, world-class research resources (researchers and facilities) to conduct research to develop therapies and identify disparities in cutaneous diseases affecting people with skin of color. HUSCRI’s current focus of clinical and basic research for skin of color is in three areas: keloids and other fibroproliferative disorders, pigmentary discorders and melanoma. HUSCRI is also exploring identification of possible link/role of alterations in genetic, epigenetic and signal pathways to observed differences in the biology of ethnic skin disorders.
Dr. Amrita Dasgupta
Risk of Cutaneous Melanoma in Skin of Color
Under the mentorship of Dr. Meena Katdare, I am working on the research project aimed towards understanding and identification of molecular markers and pathways as risk factors for cutaneous melanoma in skin of color.
The variation in human skin color arises due to differences in the quantity of a brown pigment, ‘Melanin’ present in one type of skin cells called Melanocytes; in addition to the way melanin is packaged and stored in packets called Melanosomes. Cutaneous Melanoma (CM) is a type of cancer originating from the malignant transformation of melanocytes, due to their uncontrolled growth of cells and over-production of melanin. It is reported as the 6th most common cancer in the US and is a leading cause of cancer deaths among young adults. The age-adjusted incidence rates (per 100,000) reported for melanoma are lower among Hispanics (4.5) and Blacks (1.0) compared with White non-Hispanics (21.6). Among several suggested physiological and molecular risk factors, intermittent and/or chronic ultra violet radiation (UVR) from sun-light exposure has been considered to be one of the primary environmental risk factor responsible for the initiation of malignant CM. The most deleterious effect of UVR on skin cells is chromosomal and DNA-damage that can cause uncontrolled cell growth and risk for cancer. Presence of melanin in the skin has been implicated to protect cells from UVR-induced DNA-damage. This is supported by the reports that population with moderately to heavily-pigmented skin exhibit lower incidence of CM compared to population with lightly-pigmented skin. It is thus perceived that dark-skinned individuals are less susceptible to the harmful effects of UVR. Unfortunately, this perceived low risk of CM in Hispanic and Black populations, has resulted in a delayed diagnosis, and advanced stage at presentation with poor prognosis. However, recent reports indicate a trend of 3% annual increase in the incidence rate of CM among Hispanics, similar to those reported among Whites. Such reports warrant an urgent unmet need to revisit and gain an in-depth understanding of UVR as an environmental risk factor, towards initiation and progression of CM irrespective of the color of skin.
To address this challenging UVR-induced CM, we at HUSCRI have developed novel cell-culture models to identify and validate differential susceptibility, mechanistic biomarkers, and molecular pathways leading to CM in skin of color.
Refereed Journal Publications from the Graduate & Undergraduate Research work conducted by Dr. Amrita Dasgupta
1) Dasgupta A., Udgaonkar J.B. and Das P. (2014). Multi-stage unfolding of a SH3 domain: Initial urea-filled dry globule precedes a wet globule with non-native structure. J. Phys. Chem. B. 118 (24), 6380-6392.
2) Dasgupta A., and Udgaonkar J.B. (2012). Transient non-native burial of a Trp residue occurs initially during the unfolding of a SH3 domain. Biochemistry, 51 (41), 8226–8234.
3) Dasgupta A., and Udgaonkar J.B. (2012). Four-State Folding of a SH3 domain: salt-induced modulation of the stabilities of intermediates and native state, Biochemistry, 51 (23), 4723–4734.
4) Jha S.K., Dasgupta A., Malhotra P.,and Udgaonkar J.B. (2011). Identification of multiple folding pathways of monellin using pulsed-thiol labeling and mass spectrometry, Biochemistry, 50, 3062–3074.
5) Dasgupta A., and Udgaonkar J. B. (2010). Evidence for Initial Non-specific Polypeptide Chain Collapse during the Refolding of the SH3 Domain of PI3 Kinase, J. Mol. Biol., 403, 430–445.
6) Lahiri S., Takao T., Devi P. G., Ghosh S., Ghosh A., Dasgupta A. and Dasgupta D. (2012). Association of aureolic acid antibiotic, Chromomycin A3 with Cu2+ and its negative effect upon DNA binding property of the antibiotic, BioMetals., 25(2):435-50.
Dr. Alon Mantel
Understanding molecular mechanisms that drive human skin pathology is my passion. Under the mentorship of Dr. Meena Katdare, I am involved in several projects aimed towards the identification of molecular pathways that regulate normal skin function and pathology.
More specifically, I am interested in understanding the role of mast cells in the development or progression of keloids, progressively expanding hyper-fibrotic scars that are prevalent in individuals of African descent. Our recent data suggest the presence of elevated number of mast cells within the keloid microenvironment. In the skin, mast cells are considered as a rich source of prostaglandin D2 (PGD2), a pro-inflammatory lipid mediator that is mostly implicated in allergic immune responses. Also observed was the upregulation of the PGD2 metabolizing enzyme, Aldo-keto reductase 1C3 (AKR1C3), by the keloid myofibroblasts. PGD2 has several bioactive metabolites which have been shown to mediate cell proliferation and apoptosis. This project is therefore designed to first, evaluate the effects of PGD2 and its metabolites on keloid cell viability and pro-fibrotic function, and second, to examine whether AKR1C3 can be used as a potential novel therapeutic target to treat keloids.
Additional project on hair loss in men (androgenic alopecia) involves studying the effects of PGD2 on testosterone metabolism by skin keratinocytes. The role of testosterone and its more potent metabolite, dihydrotestosterone, as drivers of androgenic alopecia is well established. The local concentration of testosterone in the skin depends in part on the expression level of various testosterone-synthesizing enzymes, thus, any chronic dysregulation of their expression may indirectly promote pathology. Recent data implicated PGD2 in promoting androgenic alopecia however, the molecular mechanism remains elusive. Our data suggest that keratinocytes stimulated with PGD2 increased their capacity to synthesize testosterone. Simultaneously, following PGD2 treatment, we observed an increase in the expression of AKR1C3 which can synthesize testosterone from the precursor androstendione. Thus, we hypothesized that increased testosterone synthesis by PGD2-treated cells may be mediated via upregulation of AKR1C3. Experiments utilizing AKR1C3 specific inhibitors and small interfering RNA are currently being conducted to validate this assumption.
Honors, Recognitions and Awards:
- Nominated and selected to participate in the 2015 Society of Investigative Dermatology PhD Retreat for Future Investigators.
- Abstract titled “Prostaglandin D2 (PGD2) enhances testosterone metabolism in primary human keratinocytes possibly via upregulation of aldo-keto reductase 1C3 (AKR1C3) expression” was selected for poster presentation in the North American Hair Research Society (NAHRS) mini-symposium. (2015)
- Albert M. Kligman Travel Fellowship Award
Society of Investigative Dermatology meeting, Albuquerque, NM (2014)
Abstract titled “The Role of Aldo-Keto Reductase 1C3 -Mediated Metabolism of Prostaglandin D2 in Keloid Fibrosis” selected for oral presentation.
- Meritorious recognition for an outstanding poster presentation, 1stplace
Skin of Color Symposium, Baltimore, MD (2013)
- Graduate Student Society Merit Award, 1st place
Recognition for an outstanding presentation of thesis work. University of Rochester, Rochester, New York (2011).
- Mantel A., Harvey V.M. P2X7/PANX1 as a new target for melanoma? Exp Dermatol. 2015 Jan 10. doi: 10.1111/exd.12633.
- Mantel A. Newsome, A. Thekuddan T. and Katdare M. The role of AKR1C3-mediated metabolism prostaglandin D2 in keloids. Experimental Dermatology (2015, accepted with revisions)
- Mantel, A., Mendini, A.B., VanBuskirk, J. and Pentland, A.P. Aldo-Keto reductase 1C3 (AKR1C3) is highly expressed in cutaneous squamous cell carcinoma (SCC) and affects SCC cell proliferation. Exp Dermatol 23(8): 573-578. (2014)
- Mantel A., Mendini, A.B, VanBuskirk, J., DeBenedetto, A., Beck, L.A. and Pentland, A.P. Aldo-keto reductase 1C3 is expressed in differentiated human epidermis, affects keratinocyte differentiation and is upregulated in atopic dermatitis. J Invest Dermatol 132(4): 1103-1110. (2012)