Dr. Susan Smyth is a physician scientist who combines clinical practice in cardiology with NIH- , VA-, and industry-funded research focused on the interplay between inflammation and thrombosis in vascular biology. Her training and expertise center around the contribution of extracellular mediators and blood and vascular cell-surface signaling receptors. Her team applies genetic and pharmacologic strategies in animal models of cardiovascular disease, in order to define cellular and molecular pathways, and then tests those pathways in clinical studies in humans. Her clinical interests are in arterial and venous thrombosis, and she leads an enterprise-wide effort in thrombosis prevention and management. She has authored more than 150 publications and contributed to over a dozen textbooks.
Smyth received her A.B. in Biology, summa cum laude, from Mount Holyoke College (South Hadley, Massachusetts), and graduated from the MD/PhD Program at the University of North Carolina (Chapel Hill, NC). As a graduate student, she studied activation of the platelet integrin αIIbβ3. After completing training in Internal Medicine, she performed cardiology subspecialty fellowship training at the Mount Sinai School of Medicine (New York, New York) and at the University of North Carolina. While a fellow at Mount Sinai, Smyth established animal models to study platelet and other cell-surface receptors in thrombosis and vascular biology. During this time, she developed an interest in understanding the interesection of thrombosis and inflammation based on observations of platelet – leukocyte interactions in models of vascular disease. Smyth joined the faculty of the University of North Carolina as an Assistant Professor of Medicine and Physiology in 2001. During her tenure at UNC, her group expanded their research to understanding of the role of bioactive, extracellular lysolipids in vascular biology. She joined the faculty of at the University of Kentucky (Lexington, Kentucky) in 2006 and currently holds appointments in the Departments of Internal Medicine, Pharmacology, Physiology, and Behavioral Sciences. Smyth is part of a research team whose work spans molecular, preclinical and clinical models, with an aim to connect discovery science to prevent cardiovascular disease and promote health.
Select Honors and Positions
- 9/83 – 5/85 A.S. (Honors), Biological Sciences, Palm Beach Jr. Coll., Lake Worth, FL
- 9/85 – 5/87 B.S. (Honors), Biological Sciences, Florida Atlantic Univ., Boca Raton, FL
- 9/88 – 6/96 Combined M.D., Ph.D. degree (Ph.D. in Microbiology/Immunology awarded 12/94,
M.D. awarded 5/96), Univ. Miami School of Medicine
Dr. D’Orazio is a physician scientist by training who combines an active clinical practice in pediatric hematology/oncology with NIH-funded research in inherited cancer syndromes, focusing on melanoma susceptibility. His training and expertise center around skin biology and molecular processes involved in UV-mediated mutagenesis and carcinogenic transformation.
Dr. D’Orazio obtained Ph.D. training in Immunology with Dr. Joan Stein-Streilein at the University of Miami, studying the effects of superantigens on natural kiler (NK) cells, publishing three first-authored works:
- D'Orazio JA, Burke GW, Stein-Streilein J. Staphylococcal enterotoxin B activates purified NK cells to secrete IFN-gamma but requires T lymphocytes to augment NK cytotoxicity. J Immunol. 1995 Feb 1;154(3):1014. (http://www.ncbi.nlm.nih.gov/pubmed/7529788)
- D'Orazio JA, Stein-Streilein J. Human natural killer (NK) cells present staphylococcal enterotoxin B (SEB) to T lymphocytes. Clin Exp Immunol. 1996 May;104(2):366-73. (http://www.ncbi.nlm.nih.gov/pubmed/8625534)
- D'Orazio JA, Cole BC, Stein-Streilein J., Mycoplasma arthritidis mitogen up-regulates human NK cell activity., Infect Immun. 1996 Feb;64(2):441-7. (http://www.ncbi.nlm.nih.gov/pubmed/8550189)
As an MD/PhD student, he then finished medical school before completing training in Pediatrics at the Massachusetts General Hospital in Boston. After spending an extra year as Chief Resident in Pediatrics, Dr. D’Orazio joined the fellowship program in Pediatric Hematology-Oncology at Boston Children’s Hospital and Dana-Farber Cancer Institute. As part of his fellowship training, Dr. D’Orazio joined the laboratory of Dr. David E. Fisher, a melanocyte biologist interested in molecular mechanisms of melanoma development. In Dr. Fisher’s laboratory, Dr. D’Orazio developed a humanized fair-skinned mouse model based on a single gene defect in the melanocortin-1 receptor (MC1R), the melanocytic cell surface receptor that, upon binding to its cognate ligand melanocyte stimulating hormone (MSH), stimulates production of the second messenger cAMP and subsequent production of pigment. Using that animal model, Drs. D’Orazio, Fisher and co-workers found that UV-dependent pigmentation (tanning of the skin) depended on MC1R function. Furthermore, they discovered that in MC1R-defective animals incapable of tanning (that approximate the fair-skinned, UV-sensitive human condition), topical application of a pharmacologic adenylate cyclase activator (forskolin) rescued robust epidermal melanin deposition that was highly protective against acute and chronic UV damage (including carcinogenesis). Their work, published in Nature in September, 2006, established MC1R as a critical mediator of epidermal UV responses. Further work from the Fisher laboratory (on which Dr. D’Orazio was a contributor) demonstrated that initiation of the MC1R signaling cascade in the skin occurs through p53 induction in UV-exposed keratinocytes. UV-mediated DNA damage in the keratinocyte subsequently leads to production of MSH from the keratinocyte compartment of the skin, and consequent up-regulation of melanocytic pigment production through the MC1R signaling cascade.
- D'Orazio JA, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K, Igras V, Kunisada T, Granter SR, Nishimura EK, Ito S, Fisher DE. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature. 2006 Sep 21;443(7109):340-4. (http://www.ncbi.nlm.nih.gov/pubmed/16988713)
- Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007 Mar 9;128(5):853-64. (http://www.ncbi.nlm.nih.gov/pubmed/17350573)
Dr. D’Orazio came to University of Kentucky in October, 2004 as Assistant Professor of Pediatrics. His laboratory has continued to investigate the role of the MC1R and downstream cAMP-dependent signaling pathways in protecting melanocytes from malignant transformation. He has focused on MC1R signaling because loss-of-function polymorphisms of MC1R (which affect millions of Americans) are associated with at least a four-fold increased lifetime melanoma risk and a much higher risk of other UV-induced skin cancers such as squamous cell and basal cell carcinomas which together account for the great majority of all cancers diagnosed annually in the United States. Since becoming independent, Dr. D’Orazio and his coworkers have reported that topical cAMP stimulation is both effective and well-tolerated in their unique murine model. Furthermore, their laboratory has become proficient in the isolation, purification and expansion of primary melanocytes and keratinocytes from the mice, facilitating mechanistic cellular studies. The D’Orazio laboratory has published several papers making use of the K14-Scf transgenic murine system, reporting that topical cAMP stimulation promotes melanin deposition in the skin and promotes epidermal thickening and UV protection.
- Amaro-Ortiz A, Vanover JC, Scott TL, D'Orazio JA. Pharmacologic induction of epidermal melanin and protection against sunburn in a humanized mouse model. J Vis Exp. 2013 Sep 7;(79). doi: 10.3791/50670. (http://www.ncbi.nlm.nih.gov/pubmed/24056496)
- Scott TL, Christian PA, Kesler MV, Donohue KM, Shelton B, Wakamatsu K, Ito S, D'Orazio J. Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation. Exp Dermatol. 2012 Oct;21(10):771-7. doi: 10.1111/exd.12012. (http://www.ncbi.nlm.nih.gov/pubmed/23078399)
- Mitra D, Luo X, Morgan A, Wang J, Hoang MP, Lo J, Guerrero CR, Lennerz JK, Mihm MC, Wargo JA, Robinson KC, Devi SP, Vanover JC, D'Orazio JA, McMahon M, Bosenberg MW, Haigis KM, Haber DA, Wang Y, Fisher DE. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature. 2012 Nov 15;491(7424):449-53. doi: 10.1038/nature11624. Epub 2012 Oct 31. (http://www.ncbi.nlm.nih.gov/pubmed/23123854)
- Murapa P, Dai J, Chung M, Mumper RJ, D'Orazio J. Anthocyanin-rich fractions of blackberry extracts reduce UV-induced free radicals and oxidative damage in keratinocytes. Phytother Res. 2012 Jan;26(1):106-12. doi: 10.1002/ptr.3510. Epub 2011 May 12. (http://www.ncbi.nlm.nih.gov/pubmed/21567508)
- Vanover JC, Spry ML, Hamilton L, Wakamatsu K, Ito S, D'Orazio JA. Stem cell factor rescues tyrosinase expression and pigmentation in discreet anatomic locations in albino mice. Pigment Cell Melanoma Res. 2009 Dec;22(6):827-38. doi: 10.1111/j.1755-148X.2009.00617.x. Epub 2009 Aug 4. (http://www.ncbi.nlm.nih.gov/pubmed/19682281)
- Chen J, Hammell DC, Spry M, D'Orazio JA, Stinchcomb AL. In vitro skin diffusion study of pure forskolin versus a forskolin-containing Plectranthus barbatus root extract. J Nat Prod. 2009 Apr;72(4):769-71. doi: 10.1021/np800541k. (http://www.ncbi.nlm.nih.gov/pubmed/19281221)
- Spry ML, Vanover JC, Scott T, Abona-Ama O, Wakamatsu K, Ito S, D'Orazio JA. Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection. Pigment Cell Melanoma Res. 2009 Apr;22(2):219-29. doi: 10.1111/j.1755-148X.2008.00536.x. Epub 2008 Dec 12 (http://www.ncbi.nlm.nih.gov/pubmed/19087231)
- Scott TL, Wakamatsu K, Ito S, D'Orazio JA. Purification and growth of melanocortin 1 receptor (Mc1r)- defective primary murine melanocytes is dependent on stem cell factor (SFC) from keratinocyte-conditioned media. In Vitro Cell Dev Biol Anim. 2009 Dec;45(10):577-83. doi: 10.1007/s11626-009-9232-3. (http://www.ncbi.nlm.nih.gov/pubmed/19633898)
Recently, the D’Orazio laboratory has focused on the role of MC1R on melanocyte genome stability. They expanded the murine model by incorporating albinism-causing tyrosinase mutations to remove MC1R-dependent pigment effects to isolate other MC1R-dependent effects on melanocytes. They found that mutagenic UV-induced photodimers were cleared more rapidly in the skin when MC1R was functional. They confirmed that MC1R-enhanced DNA repair occurred in melanocytes and that this observation extended to human melanocytes. They recently reported that MC1R signaling impacts nucleotide excision DNA repair by a novel and direct PKA-mediated phosphorylation of ATR on Ser435, an amino acid residue previously not known to affect ATR's function. Rather than activate ATR to promote Chk1 phosphorylation and cell cycle arrest, Ser435 phosphorylation by PKA promotes ATR's physical association with xeroderma pigmentosum complement group A (XPA) protein and directs XPA to sites of UV damage in the nucleus to accelerate repair of photodamage. PKA-mediated phosphorylation of ATR on Ser435, stimulated either by MSH-MC1R interactions or pharmacologically by forskolin-mediated adenylyl cyclase activation, accelerated repair of UV photodamage and robustly protects against UV-induced mutagenesis. Their findings were recently published in Molecular Cell:
- Jarrett SG, Horrell EM, Christian PA, Vanover JC, Boulanger MC, Zou Y, D'Orazio JA. PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage. Mol Cell. 2014 Jun 19;54(6):999-1011. doi: 10.1016/j.molcel.2014.05.030. (http://www.ncbi.nlm.nih.gov/pubmed/24950377)
Though his interest in small molecule-induced pigmentation (sunless tanning) continues, Dr. D’Orazio is currently focused on the molecular mechanisms by which MC1R signaling pathway enhances UV resistance in melanocytes by inducing repair of UV-induced DNA damage. The laboratory’s current research interests are to:
- Characterize the mechanisms of PKA-mediated ATR phosphorylation in MC1R-enhanced nucleotide excision repair
- Determine the regulation of epidermal MC1R ligands in human skin following UV exposure
- Define the contribution of the MC1R in melanocyte anti-oxidant pathway regulation
The intent of the D’Orazio research group is to use the information gathered from their studies to develop novel melanoma-preventive therapies based on MC1R signaling pharmacologic replacement in high-risk MC1R-defective melanoma-prone individuals.