Research team
Expertise
My job consist to uncover how loss of functional HINT1 leads to a rare form of peripheral neuropathy. To do so, I work with mammalian cells and yeast to identify disease phenotypes that can help elucidate HINT1's function. The different assays and sutdies I perform include: trasncriptomics, immunoblotting, immunhistochemistry, qPCR, cloning, yeast culture and growth curve analysis, yeast spot assay, iPSCs cultures and differentiations into motoneurons. I also performed CRISPR/Cas9 genome editing technologies to obtain knockout. Most recently I started studying the calcium signaling in different cellular models.
HINT1 neuropathies – identification of disease pathways and therapeutic targets.
Abstract
In 2012, our research group reported that genetic defects in HINT1 are associated with Charcot-Marie-Tooth neuropathy (CMT), the most common inherited disorder of the peripheral nerves. Mutations in HINT1 contribute significantly to the CMT morbidity; however the molecular mechanisms triggered by the loss of HINT1 function are unknown. The encoded protein is a purine phosphoramidase, but the physiological role of HINT1 in neurons and its connection to disease is utterly undiscovered. My project aims to understand how mutations in HINT1 lead to neurodegeneration and to translate this knowledge into therapeutic opportunities for peripheral neuropathies. The study will be performed in the Molecular Neurogenomics group led by Prof. Albena Jordanova at the VIB Department of Molecular Genetics, University of Antwerp. Taking advantage of the evolutionary conservation of HINT1 function, I will integrate studies in yeast and patient-derived model systems to identify the genetic and functional interactors of this protein. Hnt1-deficient yeasts grow normally at physiological conditions, but have reduced viability under stress. Thus, this organism has compensatory mechanisms rescuing the Hnt1 dysfunction. Similar alternative mechanisms might exist in mammals and their identification offers particular translational advantages. In a large-scale genetic complementation study, I will search for neuronally-expressed human genes rescuing the Hnt1 deficiency in yeast. The suppressor screen will be supplemented with RNA sequencing of induced neurons established from HINT1 patients. Their expression profiling will uncover neuronal transcripts mis-regulated in a disease-specific manner. The results obtained with these complementary approaches will allow me to implicate HINT1 in a network of cellular pathways and, simultaneously, to explore compensatory mechanisms that counteract the pathological effects of HINT1 deficiency. I will pharmacologically target in yeast the most suitable protein hits coming out of my combined screenings, as to provide a proof of concept. Like this, I will use the yeast model not only as a genetic tool to unravel disease etiology, but also as a pre-clinical drug discovery platform for inherited peripheral neuropathies. Ultimately, my strategy will deliver mechanistic insights into HINT1-related CMT, and will provide avenues for rational drug design to treat this devastating disorder.Researcher(s)
- Promoter: Jordanova Albena
- Fellow: Amor Barris Silvia
Research team(s)
Project type(s)
- Research Project