Cure SMA Awards $150,000 Grant to Sibylle Jablonka, PhD, University of Würzburg, Germany
Cure SMA has awarded a $150,000 research grant to Sibylle Jablonka, PhD at University of Wurzburg, for her project, “Modulation of calcium channels in mouse models for spinal muscular atrophy (SMA)”.
Dysregulated cellular mechanisms, such as neurotransmission, are complex and not well understood in SMA. Dr. Jablonka and her team have demonstrated that calcium channels which are tightly associated with active zones, the site of neurotransmitter release between neurons, are dysregulated and cluster inappropriately in SMA mouse models. They have shown that modulation of these channels re-balances dysregulated calcium homeostasis and improves functional defects in motor axon terminals. However, it is still an unsolved issue why motor neurons and neuromuscular endplates from SMA mouse models exhibit affected calcium channel-cluster formations.
This project focuses on the analysis of molecular targets whose modulation/regulation counteracts neuromuscular dysfunction in Smn-deficient motor neurons through re-balancing calcium homeostasis. External modulation of the targets could help to improve synaptic function and enhance the beneficial effects of other therapeutics.
Meet Dr. Jablonka
Who are you?
During my doctoral thesis at the Institute of Human Genetics in Hamburg (UKE, Germany) I was working on the identification of disease genes by analyzing chromosomal rearrangements in patients with mental retardation. After finishing the Ph.D. program, I started my career as a neuroscientist in the institute of clinical neurobiology in Würzburg (Germany) with a focus on motoneuron disorders, including spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress (SMARD1) and different forms of amyotrophic lateral sclerosis (ALS). Currently, I am working as a senior scientist and independent group leader in the institute.
How did you first become involved with SMA research?
After finishing my PhD thesis in human genetics (1999) I decided to extend my knowledge on motor neuron disorders. I started my post doc in the institute of clinical neurobiology in Würzburg, Germany. Since that time, I am primarily deciphering cellular and molecular dysregulations leading to different forms of spinal muscular atrophy.
What is your current role in SMA research?
Currently I am an independent group leader in the institute of clinical neurobiology in Würzburg, Germany. My group is interested in the identification and analysis of affected cellular targets as well as signaling pathways leading to motor neuron loss in two forms of spinal muscular atrophy (SMA, the proximal form of spinal muscular atrophy, and SMARD1, spinal muscular atrophy with respiratory distress type 1). Our research studies combine high resolution microscopy and life cell imaging studies with biochemical approaches preferentially performed with primary motor neurons from the different mouse models for SMA and SMARD1. The understanding of affected cellular mechanisms is the prerequisite for SMN-independent therapeutic strategies.
What do you hope to learn from this research project?
The project aims at understanding the cellular mechanisms leading to affected cluster formations of the active zone-associated voltage-gated calcium channels (VGCCs) in Smn-deficient motoneurons due to dysregulations of their auxiliary subunits. We will further expand our study on the modulation of these VGCC-subunits to compensate affected VGCC-cluster formations that in turn might support proper differentiation of and neurotransmission in SMA motor axon terminals.
How will this project work?
We will use molecular, life-cell imaging and electrophysiological assays to perform experiments on function, regulation as well as modulation of auxiliary voltage-gated calcium channel subunits. Results from subunit-knockdown experiments and subunit-targeted approaches will be visualized by confocal and high-resolution microscopy.
What is the significance of your study?
Our project promises to systematically evaluate the impact of auxiliary subunits on proper voltage-gated calcium channel cluster formations in motor axons and neuromuscular endplates. In particular, external modulation of these subunits in Smn-deficient motor neurons may provide a novel strategy to improve synaptic function in SMA.
Basic Research Funding
This grant to Dr. Jablonka is part of $1,150,000 in new basic research funding that we’re currently announcing.
Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.