My objective is to acquire advanced and working knowledge of disciplines that will help place the microarray-obtained gene expression data into a broader biological context. For a scientist interested in genomics, ideal expertise encompasses multiple neuroscience disciplines, including (but not limited to) population genetics, biostatistics and stereological assessment of the studied tissue. This additional expertise will enable me to identify complex relationships between datasets, interpret the obtained microarray data in the light of existing linkage studies, perform limited genotyping experiments on our postmortem samples and verify the uncovered gene expression changes using non-biased, stereological sampling methods. Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been associated with deficits of working memory, while functional changes in the superior temporal gyrus (STG) have been related to psychosis. Furthermore, the presentation of schizophrenia across genders has been associated with differences in age of onset, symptomathology, premorbid history, neuroimaging findings, drug responsiveness and brain structure. This application is focused around two critical questions: 1) Is there a schizophrenia-related expression profile within and across different brain regions and 2) Are schizophrenia-related expression changes different across genders? In this context, we propose to test seven specific hypotheses using 3 specific aims:
Aim1 Compare gene expression pattern in 12 MALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices.
Aim 2. Compare gene expression pattern in 12 FEMALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices.
Aims 1 and 2 will share the same methodology, and compare the transcriptomes: A) Using whole genome HG_U133A and B Affymetrix microarrays. B) Using custom-made, high-sensitivity polymer eDNA microarrays. These eDNA polymer arrays, involving our proprietary probes (patent application in progress) will allow us an improved and targeted assessment of many transcripts that are too sparse to be detected by the currently available microarrays.
Aim 3. Verify and localize the microarray-uncovered gene expression changes to cell types A) at transcript level using in situ hybridization; B) at protein level using immunohistochemistry and C) follow up the most promising expression changes with genotyping of postmortem samples.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH070786-03
Application #
7048612
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2004-04-01
Project End
2006-07-31
Budget Start
2006-04-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$28,166
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Horváth, Szatmár; Mirnics, Károly (2014) Immune system disturbances in schizophrenia. Biol Psychiatry 75:316-23
Kálmán, Sára; Garbett, Krassimira A; Vereczkei, Andrea et al. (2014) Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts. Exp Cell Res 320:343-53
Mitchell, Amanda C; Leak, Rehana K; Garbett, Krassimira et al. (2012) Physical activity-associated gene expression signature in nonhuman primate motor cortex. Obesity (Silver Spring) 20:692-8
Horvath, Szatmar; Janka, Zoltan; Mirnics, Karoly (2011) Analyzing schizophrenia by DNA microarrays. Biol Psychiatry 69:157-62
Shelton, R C; Claiborne, J; Sidoryk-Wegrzynowicz, M et al. (2011) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 16:751-62
Mitchell, Amanda C; Aldridge, Georgina; Kohler, Shawn et al. (2010) Molecular correlates of spontaneous activity in non-human primates. J Neural Transm (Vienna) 117:1353-8
Garbett, K A; Horvath, S; Ebert, P J et al. (2010) Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression. Mol Psychiatry 15:987-95
Arion, Dominique; Horvath, Szatmar; Lewis, David A et al. (2010) Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: signature of altered neural development? Neurobiol Dis 37:738-46
Lintas, C; Sacco, R; Garbett, K et al. (2009) Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry 14:705-18
Korade, Zeljka; Kenworthy, Anne K; Mirnics, Károly (2009) Molecular consequences of altered neuronal cholesterol biosynthesis. J Neurosci Res 87:866-75

Showing the most recent 10 out of 24 publications