About the Project
Mechanistic target of Rapamycin (mTOR) and regulatory protein of TOR (Raptor) complexes (mTORC1) promote idiopathic- and hypoxic pulmonary hypertension (PH), facilitating pulmonary arterial smooth muscle cell (PASMC) growth, proliferation, and thus pulmonary vascular remodelling. In 2009 we identified Two Pore Segment Channel 2 (TPC2) as a lysosome targeted ion channel. Evidence suggests that TPC2 associates with mTORC1 and may thus impact autophagy, cell metabolism and growth. Accordingly, we have now shown that mTORC1 inhibitors, which ameliorate hypoxic-PH, control lysosomal Ca2+ release through TPC2 in PASMCs, and subsequently “desensitise” TPC2, blocking further activation.
Although it is clear that lysosomes play key roles in cellular metabolism, we do not understand the precise mechanisms by which metabolic signals are received and processed by these organelles. Furthermore, while we know the genetic basis of lysosomal storage diseases that precipitate pulmonary hypertension (PH), such as Pompe disease (mutations in GAA gene) and Gaucher disease (mutations in GBA gene), how they select for pulmonary vascular dysfunction remains a mystery. What is clear is that the cell types primarily affected by Pompe disease, for example, are required, like pulmonary arterial smooth muscle cells (PASMCs), to be highly active during hypoxic stress (e.g., nerves and muscles of respiration).
Clearly, therefore, our understanding of the causes of PH will be advanced by further exploration of the cell-specific mechanisms by which lysosome function and autophagy are regulated in PASMCs. Therefore, your aim will be to determine: (1) How TPC2 interacts with and is regulated by mTORC1 in PASMCs; (2) The upstream pathways that impact mTORC1 and thus TPC2 in PASMCs; (3) How TPC2 contributes to PASMC autophagy, growth and proliferation; (4) The impact of TPC2 deletion, desensitisation and block on the progression of hypoxic-PH.
References
1. Ogunbayo OA, Duan J, Xiong J, Wang Q, Feng X, Ma J, Zhu MX and Evans A.M.. mTORC1 controls lysosomal Ca2+ release through the two-pore channel TPC2. Sci Signal. 2018;11. doi: 10.1126/scisignal.aao5775.
2. Moral-Sanz, J., Mahmoud, A.D., Ross, F.A., Eldstom, J., Fedida, D., Hardie D.G., Evans, A.M. (2016). AMP-activated protein kinase inhibits Kv1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation. J. Physiol., 594, 4901-4915.
3. Ogunbayo, O.A., Zhu, Y., Shen, B., Agbani, E., Li, J., Ma, J., Zhu, M.X., Evans, A.M. (2015). Organelle-specific Subunit Interactions of the Vertebrate Two-pore Channel Family. J. Biol. Chem., 290, 1086-1095.
4. Lin, P.H., Duann, P., Komazaki, S., Park, K.H., Li, H., Sun, M., Sermersheim, M., Gumpper, K., Parrington, J., Galione, A., Evans, A.M., Zhu, M.X., Ma, J. (2014). Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J. Biol. Chem., 290, 3377-89.
5. Fameli N., Ogunbayo O.A., van Breemen C., Evans A.M. (2014). Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling [v1; ref status: indexed, http://f1000r.es/32q] F1000Research 2014, 3:93. doi: 10.12688/f1000research.3720.1.
6. Ogunbayo O.A., Zhu Y., Rossi D., Sorrentino V., Ma J., Zhu M.X., Evans A.M. (2011). Cyclic adenosine diphosphate ribose activates ryanodine receptors, whereas NAADP activates two-pore domain channels. J. Biol. Chem., 286, 9136-9140.
7. Calcraft, P.J., Arredouani, A., Ruas, M., Pan, Z., Cheng, X., Hao, X., Tang, J., Reindorf, K., Teboul, L., Chuang, K-T, Lin, P., Rui Xiao, R., Wang, C., Lin, Y., Wyatt, C.N., Parrington, J., Ma, J, Evans, A.M., Galione, A., Zhu, M.X. (2009). NAADP targets TPC2 to release Ca2+ from lysosomal stores in mammalian cells. Nature, 459, 596-600.
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