Laboratory of Cell Physiology

Principal investigators

Philippe GAILLY, MD, PhD
Roberta GUALDANI, PhD
Nicolas TAJEDDINE, MD, PhD

Postdoctoral fellows

Thibaud PARPAITE, PhD

PhD Students

Caren JABBOUR, PhD Student

Michele ARMENIA, PhD Student

Clara BOURGY, PhD Student

Alessia ROMANIN, PhD Student

Technical staff

Mathilde BEKA, Technician

Isabelle LAMBERMONT, Technician

Xavier YERNA, Technician

Sabrina TEMPESTA, Technician

National collaborations

• Jean-Noël Octave, Pascal Kienlen-Campard and Fadel Tissir (IoNS, UCLouvain)
• Olivier Devuyst (NEFR, UCLouvain)
• Donatienne Tyteca (DDUV, UCLouvain)
• Joseph Lorent (LDRI, UCLouvain)
• Robrecht Raedt (UGent)

International collaborations

• Sulayman Dib-Hajj and Stephen Waxman (Yale University, USA)
• Thomas Ducret (Université de Bordeaux, France)
• Koji Shibasaki (University of Nagasaki, Japan)
• Ryuta Koyama (University of Tokyo, Japan)

TRPC and memory

TRPC channels are largely expressed in the brain, in particular in the hippocampus. We have shown that TRPC1 is activated in response to stimulation of mGluR5 (a type I metabotropic glutamate receptor). We investigate its role in neuronal excitability, synaptic plasticity, in memory formation and extinction. In collaboration with other groups, we have also studied how the amyloid-β precursor protein (APP) modulates synaptic activity by modifying the expression or the activity of neuronal ion transporters like the K+-Cl- cotransporter 2 (KCC2), and how this might interfere with memory processes.

Mechano- and osmo-sensitivity of TRPV channels

Systemic osmoregulation is a vital process in which brain and kidney act in concert to regulate the water concentration in the organism. We study the signaling pathways involved in the process as well as the TRP channels sensing osmotic/ mechanical stimuli. We have shown that TRPV4 has an essential role in the CNS but also in the kidney where it controls the secretion of renin (juxtaglomerular apparatus) and the reabsorption of albumin (proximal tubule).

TRP channels in pain

Several members of the TRP channel superfamily are highly expressed in the nerve endings of peripheral sensory neurons and play central roles in the development of acute and chronic pain.

Using a combination of molecular modeling and biophysical techniques, we are looking for recurrent TRP ion channel mutations in patients suffering from severe chronic pain, in order to understand whether there is a genetic predisposition to the development of the pain conditions, and to develop personalized therapies to normalize the activity of the mutant channels. In this context, we have recently analyzed two mutations of TRPM7 and TRPM8 channels found in patients with trigeminal neuralgia, and provided key structural insights into how these mutations may cause hyperexcitability of trigeminal neurons and lead to the onset of neuropathic pain.

Ca2+ entry and cancer

Store-operated Ca2+ entry (SOCE), the main pathway allowing Ca2+ influx into non-excitable cells, is involved in tumorogenesis, cancer progression and chemoresistance. We showed that depletion of stromal interaction molecule 1 (STIM1), an ER Ca2+ sensor, and TRPC1 channel, reduced the SOCE and consequently the cisplatin-induced cytotoxicity in cancer cells. In several cancer types such as glioblastoma, mechanosensitive channels seem to control proliferation, migration or invasion. We currently study how these mechanosensitive channels (some TRP isoforms but also Piezo 1) are dysregulated by the changes observed in the lipid composition of the membrane lipid bilayer.

Glioblastoma

Glioblastoma (GBM) is the most diagnosed brain cancer in adults, affecting about 1,000 patients in Belgium each year. It is a dreaded cancer with a median survival of only 12-15 months and virtually all patients suffer fatal relapse following re-growth of the tumour, even after optimal treatment. There is therefore an urgent need for a better understanding of the mechanisms underlying resistance to treatment in GBM.

Standard treatment relies on surgical debulking, the alkylating agent temozolomide (TMZ) and radiotherapy (RT). Ultimately, the principal biological effects of TMZ and RT is to kill GBM cells or stop their proliferation by inducing DNA damage beyond cellular capacity of repair.

A growing number of studies show that the DNA damage response (DDR) is involved in resistance to alkylating agents and RT, particularly in GBM. The DDR is thought to initiate DNA repair processes that increase the resistance of cancer cells to treatment. In GBM, high expression of several molecular components of the DDR is associated with TMZ and RT resistance and poor prognosis in GBM and inhibitors of the DDR are currently under pre-clinical or clinical investigation with the aim to enhance the effectiveness of chemotherapy and RT.

In our team, we focus on proteins involved in the DDR pathway that may promote chemo- and radio-resistance in GBM. We have recently discovered that the loss of certain proteins like Diaph3, which are responsible for chromosome segregation during mitosis increases aneuploidy and enhances activation of the DDR pathway. Our hypothesis is that basal activation of this pathway promotes chemo- and radio-resistance in GBM.

• Gualdani R, Seghers F, Yerna X, Schakman O, Tajeddine N, Achouri Y, Tissir F, Devuyst O, Gailly P. (2020) Mechanical activation of TRPV4 channels controls albumin reabsorption by proximal tubule cells. Science Signaling, 13(653):eabc6967. doi: 10.1126/scisignal.abc6967.
   
• Yerna X, Schakman O, Ratbi I, Kreis A, Lepannetier S, de Clippele M, Achouri Y, Tajeddine N, Tissir F, Gualdani R, Gailly P. (2020) Role of the TRPC1 Channel in Hippocampal Long-Term Depression and in Spatial Memory Extinction.
  International Journal of Molecular Sciences. 2020, 21(5), 1712; doi:10.3390/ijms21051712.
   
• A Kreis, J Desloovere, N Suelves, N Pierrot, X Yerna, F Issa, O Schakman, Roberta Gualdani, Marie De Clippele, Nicolas Tajeddine, Pascal Kienlen-Campard, Robrecht Raedt, Jean-Noël Octave, Philippe Gailly (2021) Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
  Scientific reports 11 (1), 1-18.
   
• Hoshi Y, Shibasaki K, Gailly P, Ikegaya Y, Koyama R. (2021) Thermosensitive receptors in neural stem cells link stress-induced hyperthermia to impaired neurogenesis via microglial engulfment.
  Science Advances 7(48): eabj8080. doi: 10.1126/sciadv.abj8080.
   
• Gualdani R, Gailly P, Yuan JH, Yerna X, Di Stefano G, Truini A, Cruccu G, Dib-Hajj SD, Waxman SG. (2022) A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons
  Proc Natl Acad Sci U S A. 119(38), e2119630119. doi: 10.1073/pnas.2119630119.
   
• Chehade G, El Hajj N, Aittaleb M, Alkailani MI, Bejaoui Y, Mahdi A, Aldaalis AAH, Verbiest M, Lelotte J, Ruiz-Reig N, Durá I, Raftopoulos C, Tajeddine N, Tissir F (2024) DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma.
  Front Oncol. 14:1359652. doi: 10.3389/fonc.2024.1359652.
   
• Kreis A, Issa F, Yerna X, Jabbour C, Schakman O, de Clippele M, Tajeddine N, Pierrot N, Octave J-N, Gualdani R and Gailly P. (2023) Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory.
  Front. Mol. Neuroscience 16:1081657. doi: 10.3389/fnmol.2023.1081657.