Associate ProfessorThomas Grewal

Project Opportunities

Title: LDL-cholesterol controls the role of integrins in cancer cell migration

Summary of opportunity:

This project explores the role of LDL-cholesterol in integrin trafficking and signalling, which is relevant for cancer cell migration.

Opportunity synopsis:

Cell migration is fundamental to many physiological and pathological settings such as wound healing and cancer cell metastasis. Cell migration depends on the cell surface delivery of extracellular matrix (ECM) and integrins (cell adhesion receptors composed of α and β subunits that bind to ECM). Delivery is driven by SNARE proteins, a family of small, membrane-associated proteins (e.g. Stx4, Stx6, SNAP23), that regulate transport of vesicles to the plasma membrane.

Cholesterol is an essential membrane component that determines SNARE localization and function and is indispensible for cell migration. This concept is based on artificial manipulation of cholesterol in cells. However, the lack of suitable tools to trace movement of natural cholesterol has made it impossible to put this into a physiological context. Many cancer cells accumulate large amounts of ‘bad' (Low Density Lipoprotein, LDL) cholesterol. Low ‘good' (High Density Lipoprotein, HDL) cholesterol is common in diabetic dyslipidemia and associated with impaired wound healing. Moreover, impaired LDL or HDL uptake alters cholesterol levels in the blood and its distribution in cells. However, how these cholesterol pools control SNARE localization and function in cell migration is unknown. Most cells acquire cholesterol through LDL, which is distributed along routes different from HDL or newly synthesized cholesterol. Based on our previous work, we hypothesize that LDL-cholesterol controls key events in SNARE-dependent cell migration.

Project Opportunities

Title: Targeting Rab7 and TBC1D15 to overcome mitochondrial dysfunction in neurological diseases

Summary of opportunity:

Pharmacological manipulation of contacts between mitochondria and LE/Lys could provide opportunities to improve PD, CMT2B and NPC disease. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity to correct de-regulated MCS formation in several neurological pathologies. 
PhD Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.
Masters Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.

Opportunity synopsis:

De-regulated inter-organelle communication via membrane contact sites (MCS) between mitochondria and late endosomes/lysosomes (LE/Lys) compromise mitochondrial homeostasis (fission, fusion) and function in Parkinson's disease (PD), Charcot-Marie-Tooth type 2B (CMT2B) and Niemann-Pick Type C (NPC). Mechanistically, we and others showed that GTPase-activating protein (GAP) TBC1D15 -dependent Rab7 GTPase activity is critical for MCS formation in these diseases. Small molecules increasing Rab7/TBC1D15 complex formation could promote untethering of mitochondria-LE/Lys contacts to improve PD and CTM2B (carrying Rab7 mutations) pathophysiology. On the other hand, pharmacological inhibitors blocking Rab7/TBC1D15 complex formation could ameliorate improper cholesterol transfer to mitochondria in NPC1 mutants. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity, providing opportunities to correct de-regulated MCS formation in several neurological pathologies. The objectives are:
1. Molecular modelling and virtual screening of compound libraries to identify small molecules that reduce/increase Rab7-GTP levels through inhibition/promotion of Rab7/TBC1D15 complex formation.
2. To assess small molecule candidates for their ability to restore mitochondrial function in cell models for PD, CMT2B and NPC disease.

Project Opportunities

Title: Targeting Rab7 and TBC1D15 to overcome mitochondrial dysfunction in neurological diseases

Summary of opportunity:

Pharmacological manipulation of contacts between mitochondria and LE/Lys could provide opportunities to improve PD, CMT2B and NPC disease. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity to correct de-regulated MCS formation in several neurological pathologies. 
PhD Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.
Masters Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.

Opportunity synopsis:

De-regulated inter-organelle communication via membrane contact sites (MCS) between mitochondria and late endosomes/lysosomes (LE/Lys) compromise mitochondrial homeostasis (fission, fusion) and function in Parkinson's disease (PD), Charcot-Marie-Tooth type 2B (CMT2B) and Niemann-Pick Type C (NPC). Mechanistically, we and others showed that GTPase-activating protein (GAP) TBC1D15 -dependent Rab7 GTPase activity is critical for MCS formation in these diseases. Small molecules increasing Rab7/TBC1D15 complex formation could promote untethering of mitochondria-LE/Lys contacts to improve PD and CTM2B (carrying Rab7 mutations) pathophysiology. On the other hand, pharmacological inhibitors blocking Rab7/TBC1D15 complex formation could ameliorate improper cholesterol transfer to mitochondria in NPC1 mutants. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity, providing opportunities to correct de-regulated MCS formation in several neurological pathologies. The objectives are:
1. Molecular modelling and virtual screening of compound libraries to identify small molecules that reduce/increase Rab7-GTP levels through inhibition/promotion of Rab7/TBC1D15 complex formation.
2. To assess small molecule candidates for their ability to restore mitochondrial function in cell models for PD, CMT2B and NPC disease.

----------Current Research Projects----------

Anti-cancer drug efficay in obesity

Role of LDL-induced mTOR signaling in prostate cancer

Role of LDL-cholesterol, NPC1 and annexin A6 in focal adhesion assembly and migration of cancer cells

Membrane contact sites – novel targets to reduce cholesteryl ester accumulation in metastatic prostate cancer

Role of LDL-cholesterol, NPC1 and annexin A6 in pancreatic cancer cell aggressiveness