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Project

Elucidating the physiological and patho-physiological role for the interaction of Bcl-2 proteins and the ryanodine receptor.

Ryanodine receptors (RyR) are tetrameric endoplasmic reticulum-located Ca2+ release channels mainly expressed in specific cell types and tissues such as T-cells, heart, skeletal muscle, brain and pancreas. Anti-apoptotic B cell lymphoma (Bcl)-2 proteins (such as Bcl-2 and Bcl-XL) are well known for their roles in preventing cell death. For this they rely on the presence of four Bcl-2 homology (BH) domains. The BH1, BH2 and BH3 domains form a hydrophobic cleft which can target the BH3 domains of the pro-apoptotic Bcl-2-family members thereby inhibiting their function. Besides this, Bcl-2 proteins influence intracellular Ca2+ signaling by targeting a wide array of Ca2+ transport mechanisms. As such, we recently showed that Bcl-2 via its BH4 domain is able to bind to and inhibit RyRs in both cell models and dissociated hippocampal neurons. In this project we aim to further our understanding and set out to identify potential (patho-) physiological roles for the interaction between Bcl-2 proteins and the RyR. We will first assess the effects of endogenous Bcl-2 proteins on RyRs via Bcl-2 knock out in RyR expressing cell models. After this we will study the effects of Bcl-2 knock out in both neurons and pancreatic acinar cells. Finally, increased RyR activity and also Bcl-2 have have been shown to play roles in Alzheimer’s disease, but have not been linked together in this context. We aim to validate if inhibitory effects of Bcl-2 on the RyR may impact the onset of this disease.

Date:1 Oct 2016 →  30 Sep 2019
Keywords:physiological, patho-physiological, Bcl-2 proteins, ryanodine receptor
Disciplines:Systems biology, Hematology, Laboratory medicine