Project holder looking for a partner
Main topic(s) of interest : HBP (Basic and Applied Research)
Brief description of project :
Neurodegeneration is the progressive structural/functional loss resulting in neuronal death. One of the neurodegenerative mechanisms leading apoptosis is the disruption of intracellular calcium homeostasis.
During my PhD, I aimed to understand the apoptotic mechanism of calcium homeostasis deregulation in neurons and to prevent apoptosis by suppressing subsequent events. For this purpose, in a project including my PhD thesis (TBAG-108T811), I utilized Speedy/RINGO protein which is a mitotic regulator and shown to be anti-apoptotic in the presence of p53 in U2OS cancer cells, to protect degenerated post-mitotic neurons against apoptosis. As a result, Speedy/RINGO was presented for the first time as an alternative to prevent degenerative neuronal death.
Speedy/RINGO’s anti-apoptotic effect was shown to be p53-dependent, but its neuronal mechanism is unknown. However, the available data suggest that this effect is not on p53, but on the ERK/MAPK and PI3K/AKT pathways downstream of p53 activation. It was shown that deregulating intracellular calcium homeostasis disrupts these pathways via p53. It is known that ERK/MAPK-PI3K/AKT pathways become active in neurodegeneration and when suppressed, degenerative neurons undergo apoptosis.
These indicate that abnormal calcium influx may cause apoptosis through MAPK/ERK-PI3K/AKT pathways via p53 activation. Combining this data with the findings of my PhD that Speedy/RINGO protected degenerated and p53-expressing neurons from apoptosis arises the research question of this proposal: Could Speedy/RINGO show its anti-apoptotic effect in degenerated neurons via MAPK/ERK-PI3K/AKT pathways? Being able to answer this question will provide a unique opportunity to prevent degenerative neuron death.
After starting to work as a faculty member, I conducted a project to understand the effect of Speedy/RINGO on ERK/MAPK-PI3K/AKT pathways in SH-SY5Y neuroblastoma cancer cells in which Speedy/RINGO was siRNA-suppressed and as a result, ERK/MAPK-PI3K/AKT activity and cell viability decreased. Although the data of this study give clues about the anti-apoptotic mechanism of Speedy/RINGO, all data were obtained from cancer cells and do not explain the mechanism in neurons. It is mandatory to study with primary neurons in a more detailed way to explain neuronal mechanism. To explain it, in this proposal Speedy/RINGO transfection will be performed in primary neuron cultures, then degeneration will be generated by increasing calcium influx, changes in MAPK/ERK-PI3K/AKT activity and apoptosis will be analyzed compared to control neurons.
This study will reveal the anti-apoptotic mechanism of Speedy/RINGO in degenerated neurons for the first time which comprises the originality of this proposal. Thus, a versatile molecule,Speedy/RINGO, can be utilized not only for understanding the mechanisms of neurodegeneration but also for developing effective treatment methods.
Keywords : neurodegeneration, Speedy/RINGO, neuron, apoptosis, ERK/MAPK, PI3K/AKT
Expertise sought : generating animal models for neurodegenerative diseases, peptide drug development
First Name : Aysegul
Last Name : Yildiz
Country : Turkey
E-mail address : email@example.com
Telephone : 905556423646