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A kutatási téma leírása:
The last decade saw a surge in genomic research aimed to discover novel disease pathophysiology and highlight new treatment possibilities. While successful in the case of many diseases, some central nervous system disorders, like depression and migraine seem to resist such efforts. In fact, until 2014 there were no genome wide significant polymorphisms identified behind depression and genome wide significant hits found after 2014 still fail to replicate (Gonda, Petschner et al., 2018). These failures have many reasons, among them the polygenic and, thus, highly complex genetic architecture of the diseases, the gene-gene interactions, but also that environmental factors may mask the effects of genetic variants (Gonda, Hullam et al., 2018).
An obvious solution to the problem may be the use of more complex models instead of the simplistic genetic variant-disease regressions, like gene-environment or gene-gene interaction models. They may allow for the environment or genetic variants to modulate the effects of a given genetic background. We have used such approaches in studies that provided novel insights for example into IL-1 or 5-HTTLPR gene functions (Kovacs, Eszlari et al., 2016; Culverhouse, Saccone et al., 2018).
Another solution may be the use of transcriptomics, since mRNA levels integrate, among others, effects of genetic variations, their interactions and environmental factors. Considering that there may be 93% correlation between mRNA and protein levels (Edfors, Danielsson et al., 2016), they even reflect pathophysiological changes in health and disease more appropriately by indicating important alterations in effector protein levels.
Archetypic use of these methods is to highlight novel targets for original medications through new pathophysiology mechanisms. Nevertheless, they may also be used to investigate current treatments, since a growing body of evidence indicates that genetic polymorphisms may alter the effects of current medications (Gonda, Petschner et al., 2018) and transcriptomic studies can serve novel drug discovery by highlighting new mechanisms of substances already in therapeutic use (Tamasi, Petschner et al., 2014; Petschner, Juhasz et al., 2016; Petschner, Tamasi et al., 2018).
PhD students, applying for the program, will be able to conduct genetic, genomic and gene-gene/gene-environment investigations for depression, migraine and psychiatric/psychologic phenotypes on our deep-phenotyped, EU-funded NEWMOOD population of 2400 individuals (LSHM-CT-2004-503474) and another population containing a sample of around 200 migraneurs and healthy controls. At the same time, through analysis of RNA-seq data in such populations PhD students can also acquire skills in the use of the most up-to-date method of transcriptomics. In addition to our human samples, found targets and antidepressants with new mechanisms can be validated in animal models using stress paradigms, behavioral tests and transcriptomics. All these approaches aim to yield novel molecular targets for novel drug discovery and provide biomarkers for current treatments’ efficacy in polygenic central nervous system disorders.
References:
Culverhouse, R.C., Saccone, N.L., Horton, A.C., Ma, Y., Anstey, K.J., Banaschewski, T., Burmeister, M., Cohen-Woods, S., Etain, B., Fisher, H.L., Goldman, N., Guillaume, S., Horwood, J., Juhasz, G., Lester, K.J., Mandelli, L., Middeldorp, C.M., Olie, E., Villafuerte, S., Air, T.M., Araya, R., Bowes, L., Burns, R., Byrne, E.M., Coffey, C., Coventry, W.L., Gawronski, K.a.B., Glei, D., Hatzimanolis, A., Hottenga, J.J., Jaussent, I., Jawahar, C., Jennen-Steinmetz, C., Kramer, J.R., Lajnef, M., Little, K., Zu Schwabedissen, H.M., Nauck, M., Nederhof, E., Petschner, P., Peyrot, W.J., Schwahn, C., Sinnamon, G., Stacey, D., Tian, Y., Toben, C., Van Der Auwera, S., Wainwright, N., Wang, J.C., Willemsen, G., Anderson, I.M., Arolt, V., Aslund, C., Bagdy, G., Baune, B.T., Bellivier, F., Boomsma, D.I., Courtet, P., Dannlowski, U., De Geus, E.J.C., Deakin, J.F.W., Easteal, S., Eley, T., Fergusson, D.M., Goate, A.M., Gonda, X., Grabe, H.J., Holzman, C., Johnson, E.O., Kennedy, M., Laucht, M., Martin, N.G., Munafo, M.R., Nilsson, K.W., Oldehinkel, A.J., Olsson, C.A., Ormel, J., Otte, C., Patton, G.C., Penninx, B., Ritchie, K., Sarchiapone, M., Scheid, J.M., Serretti, A., Smit, J.H., Stefanis, N.C., Surtees, P.G., Volzke, H., Weinstein, M., Whooley, M., Nurnberger, J.I., Jr., Breslau, N., and Bierut, L.J. (2018). Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol Psychiatry 23, 133-142.
Edfors, F., Danielsson, F., Hallstrom, B.M., Kall, L., Lundberg, E., Ponten, F., Forsstrom, B., and Uhlen, M. (2016). Gene-specific correlation of RNA and protein levels in human cells and tissues. Mol Syst Biol 12, 883.
Gonda, X., Hullam, G., Antal, P., Eszlari, N., Petschner, P., Hokfelt, T.G., Anderson, I.M., Deakin, J.F.W., Juhasz, G., and Bagdy, G. (2018). Significance of risk polymorphisms for depression depends on stress exposure. Sci Rep 8, 3946.
Gonda, X., Petschner, P., Eszlari, N., Baksa, D., Edes, A., Antal, P., Juhasz, G., and Bagdy, G. (2018). Genetic variants in major depressive disorder: From pathophysiology to therapy. Pharmacol Ther.
Kovacs, D., Eszlari, N., Petschner, P., Pap, D., Vas, S., Kovacs, P., Gonda, X., Juhasz, G., and Bagdy, G. (2016). Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress. Brain Behav Immun 56, 96-104.
Petschner, P., Juhasz, G., Tamasi, V., Adori, C., Tothfalusi, L., Hokfelt, T., and Bagdy, G. (2016). Chronic venlafaxine treatment fails to alter the levels of galanin system transcripts in normal rats. Neuropeptides 57, 65-70.
Petschner, P., Tamasi, V., Adori, C., Kirilly, E., Ando, R.D., Tothfalusi, L., and Bagdy, G. (2018). Gene expression analysis indicates reduced memory and cognitive functions in the hippocampus and increase in synaptic reorganization in the frontal cortex 3 weeks after MDMA administration in Dark Agouti rats. BMC Genomics 19, 580.
Tamasi, V., Petschner, P., Adori, C., Kirilly, E., Ando, R.D., Tothfalusi, L., Juhasz, G., and Bagdy, G. (2014). Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes. PLoS One 9, e113662.
Jelentkezési határidő: 2021-02-20 |
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