Research projects
Project 1:
Biological and Genetic Markers in Anxiety and Depression
Samantha Segall, Ph.D.
Genetics Medicine Building, Room 1022E
email:Segall@email.unc.edu
Research Project 2: COMT:
Comt1 Genotype and Expression Predicts Anxiety and Nociceptive Sensitivity in Inbred Strains of Mice.
Segall SK, Nackley AG, Diatchenko L, Lariviere WR, Lu X, Marron JS, Grabowski-Boase L, Walker JR, Slade G, Gauthier J, Bailey JS, Steffy BM, Maynard TM,Tarantino LM, Wiltshire T.
Curriculum of Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA.
Abstract
Catechol-O-methyltransferase (COMT) is an ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity (Andersen & Skorpen, 2009) and risk for developing psychiatric disorders (Harrison & Tunbridge, 2008). A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation (Nackley et al., 2006). However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have assessed Comt1 gene expression levels in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed among the strains, and this differential expression is cis-regulated. A B2 Short Interspersed Element (SINE) was inserted in the 3'UTR of Comt1 in 14 strains generating a common haplotype that correlates with gene expression. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element demonstrate that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3'UTR B2 SINE element, regulates Comt1 expression and some mouse behaviors
Oscar Suzuki, Ph.D, postdoctoral Researcher,
Genetic Medicine Building Rm 1022 F
Project 3: MEF
Cellular Genetics Approaches in Defining Drugs Toxicity Pathways
Our project involves identification of genetic components contributing to drug toxicity. For this, we are using high content imaging of cultured primary embryonic fibroblasts to screen 32 inbred strains of mice for variations in several cell phenotypes related to the toxic response - cell loss, nuclear morphology, cell membrane permeability, mitochondrial membrane potential and cytochrome c localization. Genotype-phenotype combinations then used to perform genome-wide association analysis to identify loci influencing the cellular effects of tested compounds.
Amber Frick ,Pharm.D. PhD. Candidate
UNC Eshelman School of Pharmacy
University of North Carolina
Campus Box 7569
Chapel Hill, NC 27599
E-mail: adfrick@email.unc.edu
Phone: 919-966-5993
Fax: 919-966-5863
Research project : 4
Cancer chemotherapy: elucidating genetic pathways for efficacy and lymphocyte toxicity
We are examining how genetically diverse mouse embryonic fibroblasts and splenic lymphocytes respond to toxicological or pharmaceutical challenge. Following high content imaging, cellular phenotypes are examined via parameters including cell loss, nuclear size, DNA content, cell permeability, mitochondrial membrane potential, and cytochrome C release. Aims include characterizing the phenotype of B- and T-lymphocytes from a panel of inbred mouse strains following exposure to chemotherapeutic agents, specifically anthracycline and platinum-based compounds, and determining genetic reasons for phenotypic differences in toxicity among these strains, integrating therapeutically relevant knowledge into pathway analyses.
Genetic Medicine Building
Rm. 1022F
120 Mason Farm Road, CB 7361
Chapel Hill, NC 27599-7361
emchan@email.unc.edu
Telephone: (919) 843-8817
Fax: (919) 966-5863
Determination of Genetic Components of Oxaliplatin -Induced Peripheral Neuropathy in Mouse Model (CIPN).
This research project will investigate and examine the genetics (DNA synthesis in cancer cells) as well as cellular components influencing therapeutic outcomes in cancer treatment (tumor cells), primarily cytotoxicological challenges induced by platinum administration among cancer patients.
Wiltshire Lab will use the Mouse as a model in this study to quantitatively measure behavior for Oxaliplatin -Induced Peripheral Neuropathy. The study will also take the extra step to qualitatively measure noceciptive effects at the baseline and drug treatment level. This can be accomplished by using open field to test the gross locomotor, sensorimotor activity levels. Other methods such as the wire hang test will also be employed to evaluate motor function in relation to the CNS deficit in rodents before and after the administration of the platin compound.
The compound qualitative measurement will involve the use of both Hot and Cold plates to quantitatively measure the extent of thermal nociceptive response in Mice. The presence or the deficit of such responses in the rodent CNS will be our central theme in determining these underlying genetic components surrounding Oxaliplatin Induced Peripheral Neuropathy.
