Daniel Hardy
Assistant Professor
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PH.D. The University of Western Ontario |
The main focus of my laboratory is investigating the role of nuclear receptors in fetal programming. While emerging epidemiological evidence suggests that the risks of adult onset diseases are inversely related to birth weight, very little is known about the genetic and/or epigenetic changes which underlie these alterations in fetal and postnatal development. Numerous animals models including maternal caloric and/or nutrient restriction, along with chemically induced gestational diabetes, hypoxia, LPS-invoked inflammation, glucocorticoid exposure, and decreased dietary protein have broadened our understanding how in utero insults may lead to restricted fetal growth. However, understanding the overall role of transcription factors involved in mediating these developmental abnormalities would provide us with better strategies in preventing the onset of adult diseases in mammals. Nuclear receptors represent the largest family of transcription factors found in metazoans, binding to steroid hormones, fat-soluble vitamins, along with oxysterols and bile acids from the diet. Although the roles of many nuclear receptors are well defined, very little is known about their function in fetal programming, which leads to permanent changes in physiological and/or metabolic processes in adulthood. In my laboratory, we use 'candidate transcription factor' approaches to examine the roles of lipid-sensing nuclear receptors in various models of fetal programming. One such model includes maternal protein restriction, which leads to lower birth weight, impaired offspring growth, decreased liver to body ratio, and an increase in fetal liver cholesterol concentrations. To address the molecular mechanisms underlying these ‘programmed' changes in nuclear receptor binding and downstream target genes, we employ chromatin immunoprecipitation (ChIP) in tissues and in cells to examine the in vivo binding of nuclear receptors to their respective promoters throughout fetal development. This helps us identify the crucial subset of lipid-sensing nuclear receptors underlying these fetal programming events. Moreover, the use of ChIP in vivo and in vitro further enhances our understanding of how epigenetic modifications are involved in the coordinated control of gene transcription during normal and abnormal fetal development.
Hardy DB, Janowski BA, and CR Mendelson. Progesterone Receptor (PR) Inhibits Aromatase and Inflammatory Response Pathways in the Breast via Ligand-Dependent and Ligand-Independent Mechanisms, Molecular Endocrinology, in press. Schwartz JC, Younger ST, Nguyen R, Hardy DB, Prakash TP, Bhat B, Monia BP, Corey DR, and Janoswski BA. Antisense Transcripts are Targets for Activating Small RNAs, Nature Structural and Molecular Biology, in press. Janowski BA, Younger ST, Hardy DB, Ram R, Nguyen R, Huffman KE, and Corey DR. (2007) Activating gene expression in mammalian cells by promoter-targeted duplex RNAs. Nature Chemical Biology. 3: 166-173. Mendelson CR, Condon JC, and Hardy DB. (2007) Regulation of Inflammatory Response Pathways During Pregnancy and Labor. In: Preterm Birth: Mechanisms, Mediators, Prediction & Interventions (Petraglia, Strauss, Gabbe, & Weiss, eds.) Hardy DB and Mendelson CR (2006) Progesterone Receptor (PR) Antagonism of the Inflammatory Signals Leading to Labor. Fetal and Maternal Medicine Review. 17(4): 281-299. Hardy DB, Janowski BA, Corey DR, and Mendelson CR (2006) Progesterone Receptor Plays a Major Anti-inflammatory Role in Human Myometrial Cells by Antagonism of NF-kB Activation of Cyclooxygenase 2 (COX-2) Expression, Molecular Endocrinology. 20(11): 2724-2733.
