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Faculty Detail     Name LAURA TIMARES   Campus Address SHEL 503 Zip 2182 Phone 205-934-7545 E-mail timares@uab.edu Other websites http://main.uab.edu/uasom/2/show.asp?durki=69364

Faculty Appointment(s) Appointment Type Department Division Rank Primary  Dermatology  Dermatology Associate Professor Secondary  Cell, Developmntl, & Integrative Biology  Cell, Developmntl, & Integrative Biology Associate Professor Secondary  Medicine  Med - Div of Human Gene Therapy Assistant Professor Secondary  Pathology   Pathology Chair Office Assistant Professor Center  Arthritis & Musculoskeletal Diseases Center  Arthritis & Musculoskeletal Diseases Center Associate Professor Center  Comprehensive Cancer Center  Comprehensive Cancer Center Associate Professor Center  Medicine  Gene Therapy Center Associate Professor

Graduate Biomedical Sciences Affiliations Cancer Biology  Cellular and Molecular Biology Program  Immunology  Medical Scientist Training Program  Pathobiology and Molecular Medicine

Biographical Sketch  Laura Timares, Assistant Professor in the Department of Dermatology, completed her undergraduate studies in biology at the University of California, Los Angeles (B.S. in Biology, 1982). Her graduate work in tumor immunology was carried out in the School of Medicine at UCLA (Ph.D.,1990). Her postdoctoral training at the California Institute of Technology (1991-1993) focused on the molecular biology of transplantation molecules. At Cedars Sinai Medical Center (Los Angeles, 1993-1996) her interests focused on genetic engineering of transplantable cells for treating liver diseases and diabetes. After joining the University of Texas, Southwestern Medical Center at Dallas in 1996, she became faculty in the Department of Medicine in the Center for Biomedical Inventions. There she studied the role of transfected dendritic cells of the skin in mediating immune responses generated from genetic immunization by gene gun. She joined UAB in 1999 where she pursues her interest in understanding the function of genetically modified dendritic cells.

Society Memberships Organization Name Position Held Org Link The American Association of Immunologists  Member  http://www.aai.org/  The Society of Investigative Dermatology  Member  http://www.sidnet.org/

Research/Clinical Interest Title Cutaneous immunology, vaccinology and carcinogenesis Description We are interested in understanding the biology of skin-derived DCs, termed Langerhans cells (LCs), so that we may learn how to harness their function in the development of “next generation” topical vaccines for combating or protecting against cancer development in skin or other organs. This subset of DCs specializes in delivering cutaneous antigens to draining lymph nodes where, depending on the environmental cues they received in the periphery (affected skin site), they are able to orchestrate tolerogenic or immunogenic responses. Recently, we discovered that murine LCs specifically undergo cell death following successful antigen presentation to naïve T cells and this limits their immunogenic potential to combat infectious diseases or cancer. We have shown that LC apoptosis depends on the pro-apoptotic molecule Bid; Bid-deficient LCs are resistant to T cell-induced death as well as mechanisms of UV radiation-induced tolerance and perform as superior vaccinating agents. How such gene-modified, apoptosis-resistant DCs induce enhanced T cell responses, evade induction of regulatory T cell (Treg) development, and what molecular signals are used by T cells to trigger DC death are under current investigation. Using LC-deficient mutant mouse strains we will test the role of LCs in mediating tolerance and in protection or promoting skin carcinogenesis. We have developed a DNA-based topical vaccine, which induces effective immunity toward a point mutation epitope of the Ras proto-oncogene commonly associated with skin neoplasias. The immunity generated against this single epitope is able to reduce tumor burden by 65%. This proof of concept study in mice has emboldened us to pursue translational studies of immunopreventative cancer vaccines for human application (in collaboration with Dr. C.A. Elmets). We are also developing murine models of spontaneous melanoma to investigate mechanisms of melanoma initiation and progression, and to identify candidate oncogene mutations, so that we can similarly develop and test the efficacy of a protective melanoma vaccine. We have also shown that epidermal keratinocytes depend on Bid expression to protect against the development of UV-induced cutaneous neoplasias. We have evidence that Bid has a novel pro-survival function that is necessary for G2/M cell cycle checkpoint activity to promote DNA repair after UV damage. We are investigating this novel mechanism by which Bid promotes cell survival in normal and skin tumor cells, with the hope of identifying a new pathway that may be prove useful as a target for cancer therapeutics. We are currently collaborating with Dr. M. Athar (UAB) to explore cooperative mechanisms that may exist between Bid and p53, as such interdependencies may identify novel therapeutic targets for treating or inhibiting cancer incidence, growth and/or progression. In addition, we are testing novel adenoviral vectors (generated by D.T. Curiel) that target delivery of genes to dendritic cells and epidermal skin cells to modulate the immune system or ameliorate disease, in canine melanoma (B. Smith, Auburn University, AL) and HIV specific immunity in guinea pigs (Q. Matthews, UAB).

Selected Publications  Publication PUBMEDID Nasti TH, Timares L. Inflammasome activation of IL-1 family mediators in response to cutaneous photodamage(†). Photochem Photobiol. 2012 May 26. doi: 10.1111/j.1751-1097.2012.01182.x  22631445  Hangalapura BN, Timares L, Oosterhoff D, Scheper RJ, Curiel DT, de Gruijl TD. CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J Gene Med. 2012 Jan 7. doi: 10.1002/jgm.1648.  22228547  Xu J, Timares L, Heilpern C, Weng Z, Li C, Xu H, Pressey JG, Elmets CA, Kopelovich L, Athar M. Targeting wild-type and mutant p53 with small molecule CP-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis. Cancer Res. 2010 Aug 15;70(16):6566-76. Epub 2010 Aug 3.  20682800  Matthews QL, Fatima A, Tang Y, Perry BA, Tsuruta Y, Komarova S, Timares L, Zhao C, Makarova N, Borovjagin AV, Stewart PL, Wu H, Blackwell JL, Curiel DT. HIV antigen incorporation within adenovirus hexon hypervariable 2 for a novel HIV vaccine approach. PLoS One. 2010 Jul 27;5(7):e11815.  20676400   Thacker EE, Nakayama M, Smith BF, Bird RC, Muminova Z, Strong TV, Timares L, Korokhov N, O'Neill AM, de Gruijl TD, Glasgow JN, Tani K, Curiel DT. A genetically engineered adenovirus vector targeted to CD40 mediates transduction of canine dendritic cells and promotes antigen-specific immune responses in vivo. Vaccine. 2009 Nov 23;27(50):7116-24. Epub 2009 Sep 26.  19786146  Thacker EE, Timares L, Matthews QL. Strategies to overcome host immunity to adenovirus vectors in vaccine development. Expert Rev Vaccines. 2009 Jun;8(6):761-77.  19485756  Pradhan S, Kim HK, Thrash CJ, Cox MA, Mantena SK, Wu JH, Athar M, Katiyar SK, Elmets CA, Timares L. A critical role for the proapoptotic protein bid in ultraviolet-induced immune suppression and cutaneous apoptosis. J Immunol. 2008 Sep 1;181(5):3077-88.  18713978  Timares, L., S. K. Katiyar, C. A. Elmets. 2008. DNA Damage, Apoptosis and Langerhans Cells-Activators of UV-induced Immune Tolerance. Photochemistry & Photobiology 84(2):422-436.   18248501  Pradhan S, Genebriera J, Denning WL, Felix K, Elmets CA, Timares L. CD4 T cell-induced, bid-dependent apoptosis of cutaneous dendritic cells regulates T cell expansion and immune responses. J Immunol. 2006 Nov 1;177(9):5956-67.  17056520  McGuire MJ, Sykes KF, Samli KN, Timares L, Barry MA, Stemke-Hale K, Tagliaferri F, Logan M, Jansa K, Takashima A, Brown KC, Johnston SA. A library-selected, Langerhans cell-targeting peptide enhances an immune response. DNA Cell Biol. 2004 Nov;23(11):742-52.  15585132   First Prev   1 2 of  2  Next Last

Keywords dendritic cells, Langerhans cells, vaccines, adjuvants, skin carcinogenesis

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