KRATEK OPIS PROJEKTA
Velika depresivna motnja (MDD) je eden najpogostejših vzrokov invalidnosti v Evropi, medtem ko je samomor glavni vzrok nasilne smrti med mladimi odraslimi. MDD in samomorilnost skupaj predstavljata (včasih se prekrivata) psihopatologiji, katerih biološka osnova je slabo razumljena, vendar ima velik negativen vpliv na družbo. Oba imata pomembno genetsko ozadje, vendar je to kompleksno in zelo heterogeno. Kot komplementarni pristop zato skupina iz Reke kot pionirji preučujejo te psihopatologije kot proteinopatije: motnje, pri katerih se specifični proteini napačno zvijejo in združujejo v možganih. Do sedaj je bilo identificiranih več takih proteinov.
V predlaganem projektu naša sodelovalna skupina interdisciplinarno pristopa k preučevanju teh agregacijskih dogodkov, njihovih vzrokov in posledic. Glede na to, da agregacija verjetno izhaja iz kombinacije genetskih in okoljskih dejavnikov, želimo z uporabo genetskih in epigenetskih pristopov ugotoviti, ali se izražanje teh proteinov razlikuje pri umrlih zaradi samomora v primerjavi z kontrolno skupino oseb in ali lahko pri teh posameznikih obstajajo specifične redke mutacije s potencialom povzročanja agregacije. Na ravni proteinov bomo uporabili biofizikalne pristope za preučevanje mehanizmov agregacije enega izmed predhodno identificiranih proteinov, TROIBP-1. V širšem smislu bomo proučevali vpliv stresa na agregacijo v celični kulturi in kako se lahko takšni proteinski agregati prenašajo med celicami. Preučeni bodo tudi novi potencialni agregacijski proteini, z namenom potrditve upravičenosti nadaljnjih študij v zvezi s proteinopatijo. Ključni izsledki preučenih agregacijskih proteinov bodo analizirani tudi v živalskem modelu sadne mušice Drosophila, da bomo ugotovili učinke teh proteinov, genetike in stresa na vedenje.
S predlaganim projektom želimo pospešiti inovativen pristop k raziskovanju MDD in samomorilnosti, ter tako prispevati k izboljšanemu prepoznavanju, diagnosticiranju in zdravljenju teh stanj.
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DeSPERADo: Depression, suicide and proteinopathy: elucidating the relationships between aggregation and pathological development
Major depressive disorder (MDD) is one of the largest causes of disability in Europe, while suicide is the leading cause of violent death amongst young adults. Together, MDD and suicidal tendency represent (sometimes overlapping) psychopathologies whose biological basis is poorly understood, but which have a major negative impact on society. Both have significant genetic backgrounds, however these are complex and highly heterogeneous. As a complementary approach, we are therefore pioneering the study of these psychopathologies as proteinopathies: disorders in which specific proteins misfold and aggregate in the brain, and have identified several such proteins.
In this project, our collaborative group takes an interdisciplinary approach to studying these aggregation events, their causes and consequences. Given that aggregation likely arises from a combination of genetic and environmental factors, we propose to employ genetics and epigenetic approaches to determine whether expression of these proteins differs in suicide victims from control individuals, and whether specific rare mutations might exist in these individuals with the potential to cause aggregation. At the protein level, we will employ biophysical approaches to study the mechanisms of aggregation of one such protein, TROIBP-1. More broadly, we will study the effect of stress on aggregation in cell culture and how such protein aggregates may transmit from cell-to-cell. Novel potential aggregating proteins, will also be characterised to determine if they warrant further study in this regard to proteinopathy. Finally, key results from these proteins will be taken into the fruit fly Drosophila, to determine the effects of these proteins, genetics and stress on behaviour.
We therefore aim to advance an emerging and exciting approach to MDD and suicidal tendency research, with the aim ultimately of improving identification, diagnosis and treatment of these conditions.