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Daret St. Clair, PhD

Cancer Center Member
Markey Research Programs:
    Redox Injury and Repair

Associate Director for Basic Research and Co-Leader, Redox Injury and Repair Research Program

James Graham Brown Foundation Endowed Chair
Professor

Graduate Center for Toxicology
College of Medicine

Research Focus

Dr. St. Clair’s research focuses on investigating the fundamental mechanisms by which reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to normal tissue injury and cancer formation. Her laboratory is the first to clone the human gene for the primary superoxide removal enzyme in the mitochondria, manganese superoxide dismutase (MnSOD), and this initial study has been expanded into several separate but related projects. These projects involve evaluating genetic abnormalities of antioxidant enzymes, the mechanisms regulating gene expression, and the impact these alterations have on the ability of humans to cope with oxidative stress. She has made the seminal observation that expression of MnSOD suppresses neoplastic transformation and promotes differentiation of cancer cells, leading to a reduction in the tumorigenicity and metastatic capability of cancer cells. Her work has led to a paradigm shift in the thinking about the role of antioxidants in cancer therapy.  

Chemotherapy-induced side effects to normal tissues are a major problem limiting the success of cancer therapy. The ability of normal tissues to tolerate these side effects frequently imposes a limit on the dose of the anticancer agent that can be given safely to the patient, which in turn limits the probability of a cure. Dr. St. Clair has recently expanded her research in the area of antioxidant defense into a program project on the role of oxidative stress in drug-induced normal tissue injury including chemotherapy-induced cognitive impairment. 

Therapy-induced acute myeloid leukemia (t-AML), therapy-induced myelodysplastic syndrome (t-MDS), and therapy-induced myeloproliferative neoplasm (t-PMN), are increasingly common in patients receiving radiation or chemotherapy, due, in part, to increasingly aggressive cancer treatments. It has been shown that radiation and nearly fifty percent of the current FDA-approved chemotherapeutic drugs exert a tumor killing effect, in part, by generation of ROS. Depending on the levels of ROS and the local cellular environment, ROS can exhibit cytotoxic or cytoprotective effects by regulating cellular signaling pathways. An important mediator of ROS-mediated action is the proinflammatory cytokine tumor necrosis factor (TNFa), which has been shown to play an important role in the development of t-MDS. Dr. St. Clair is investigating how hematopoietic stem cells (HSC) and hematopoietic precursor cells (HPC) differentially utilize the ROS-mediated signals to trigger development of t-MDS and subsequent progression to leukemia.  

Contact Information

1095 VA Drive
458 HSRB
University of Kentucky
Lexington, Kentucky 40536
859-257-3956
dstcl00@uky.edu

Key Publications

  1. Yen HC, Oberley TD, Vichitbanda S, Ho YS, St. Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest 98:1253-1260, 1996.
  2. Majima HJ, Oberley TD, Furakawa K, Mattson MP, Yen HC, Szweda LI, St. Clair DK. Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. J Biol Chem 273:8217-8224, 1998.
  3. Zhao Y, Chaiswing L, Oberley TD, Batinic-Haberle I, St. Clair WH, Epstein CJ, St. Clair DK. A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res 65:1401-1405, 2005.
  4. Lien YC, Noel T, Liu H, Stromberg AJ, Chen KC, St. Clair DK. Phospholipase C-delta1 is a critical target for TNF receptor-mediated protection against adriamycin-induced cardiac injury. Cancer Res 66:4329-4338, 2006.
  5. Dhar SK, Tangpong J, Chaiswing L, Oberley TD, St. Clair DK. Manganese superoxide dismutase is a p53-regulated gene that switches cancers between early and advanced stages. Cancer Res. 71:6684-6695, 2011.

Five Most Recent Publications (an automated list via PubMed, based on researcher's ID and University of Kentucky)

1.  Xu Y, Miriyala S, Fang F, Bakthavatchalu V, Noel T, Schell DM, Wang C, St Clair WH, St Clair DK.
Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect.
Oncogene. 2014 Nov.
2.  Zhao Y, Miriyala S, Miao L, Mitov M, Schnell D, Dhar SK, Cai J, Klein JB, Sultana R, Butterfield DA, Vore M, Batinic-Haberle I, Bondada S, St Clair DK.
Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment.
Free Radic Biol Med. 2014 Jul;72:55-65.
3.  Holley AK, Xu Y, Noel T, Bakthavatchalu V, Batinic-Haberle I, St Clair DK.
Manganese superoxide dismutase-mediated inside-out signaling in HaCaT human keratinocytes and SKH-1 mouse skin.
Antioxid Redox Signal. 2014 May;20(15):2347-60.
4.  Breckwoldt MO, Pfister FM, Bradley PM, Marinković P, Williams PR, Brill MS, Plomer B, Schmalz A, St Clair DK, Naumann R, Griesbeck O, Schwarzländer M, Godinho L, Bareyre FM, Dick TP, Kerschensteiner M, Misgeld T.
Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo.
Nat Med. 2014 May;20(5):555-60.
5.  Holley AK, Miao L, St Clair DK, St Clair WH.
Redox-modulated phenomena and radiation therapy: the central role of superoxide dismutases.
Antioxid Redox Signal. 2014 Apr;20(10):1567-89.