Angelika Lampert (RWTH Aachen University, Germany.)
"iPS-cell derived nociceptors to study the pathophysiology of pain-linked sodium channel mutations"
Chronic neuropathic pain treatment still is a therapeutic challenge and mechanistically based individual treatment is not available. Genetically encoded pain syndromes offer the chance to study mechanisms of chronic pain on a cellular level: induced pluripotent stem cells (iPSC) from patients carrying pain-causing mutations can be reprogrammed and differentiated into nociceptors in the dish. This system allows us to study the role of voltage gated sodium channels, e.g. Nav1.7, in action potential firing. Using patch-clamp electrophysiology, we find that Nav1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes to the action potential upstroke.
Ultimately, our goal is to identify personalized medicine for individual, treatment-resistant patients using iPSC derived nociceptors. In a case of a Caucasian patient suffering from severe small fiber neuropathy (SFN), we can report a first example of in-vitro predicted individualized treatment success. Using iPSC-derived patient nociceptors, we can identify patient specific firing patterns which can be directly correlated to clinical findings. Multi-electrode array recordings and transcriptomic approaches support diagnostics and functional/genetic characterization on a cellular level. This approach could open a way for successful companion diagnostics and personalized medicine.
Angelika Lampert, MD, is a full professor in the Institute of Physiology (Neurophysiology) at the RWTH Aachen University, Germany.
Johan Auwerx (Laboratory of Integrative Systems Physiology - EPFL)
"Cross species of genetics to identify targets in mitochondria and aging"
Our understanding of genetic mechanisms that define complex traits has been hindered by the difficulty of obtaining comprehensive omics datasets across a broad range of biological “layers”. Complete data on the genome of individuals can be readily obtained, but the full complexity of the transcriptome, proteome, metabolome, and phenome have remained largely out of reach. This is, however, beginning to change, with the development of robust multi-layered omics strategies that are pioneered in model organisms. We here profiled the healthspan in >80 cohorts of the BXD mouse genetic reference population. Large variability was observed across all omics layers; to understand how these differences stem from genetic variance, we exploited a multilayered set of molecular phenotypes—genomics, transcriptomics, proteomics, and metabolomics. With this multi-omics strategy, large networks of proteins could be analyzed and causal variants identified in proteins involved in determination of lifespan (e.g. Mrps5, Jmjd3), hypertension (Ubp1) and in mitochondrial metabolism (e.g. Dhtkd1, Cox7a2l). These new candidates were then validated using cross-species genetic strategies in C. elegans, mouse, and human. Our large-scope multi-omics measurements in mouse populations combined with cross-species validation hence provided us with robust conserved and mechanistically defined pathways that underpin complex traits involved in metabolism and aging.
Johan Auwerx is Professor at the École Polytechnique Fédérale in Lausanne, Switzerland
Angelika Lampert, MD, is a full professor in the Institute of Physiology (Neurophysiology) at the RWTH Aachen University, Germany.
She is the coordinator of the Sodium Channel Network Aachen (SCNAachen) focusing on inherited neuropathic pain syndromes such as small fiber neuropathy linked to sodium channel mutations. Her research concentrates on the translation of laboratory findings to potential clinical treatment, either as a population therapy or personalized medicine.
The Lampert lab has two main focuses: 1) biophysics and structure-function relation of voltage-gated sodium channels and their mutations linked to pain, and 2) induced pluripotent stem cells (iPS-cells) and their differentiation into peripheral sensory neurons as a model for human neuropathies in the dish.
Dr. Lampert studied human medicine in Jena, Germany, and Strasbourg, France, and completed her MD thesis at the Max-Plank working group Molecular and Cellular Biophysics in Jena in 2003. Following postdoctoral training with Dr. Stephen G. Waxman at Yale University in New Haven, CT, Angelika Lampert set up her lab in Erlangen, Germany, before moving to Aachen in 2013. Dr. Lampert is the recipient of awards and grants from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF) and the German Association of the Study of Pain (DGSS).
Johan Auwerx is Professor at the École Polytechnique Fédérale in Lausanne, Switzerland, where he occupies the Nestle Chair in Energy Metabolism. Dr. Auwerx has been using molecular physiology and systems genetics to understand metabolism in health, aging and disease. Much of his work focused on understanding how diet, exercise and hormones control metabolism through changing the expression of genes by altering the activity of transcription factors and their associated cofactors. His work was instrumental for the development of agonists of nuclear receptors - a particular class of transcription factors - into drugs, which now are used to treat high blood lipid levels, fatty liver, and type 2 diabetes. Dr. Auwerx was amongst the first to recognize that transcriptional cofactors, which fine-tune the activity of transcription factors, act as energy sensors/effectors that influence metabolic homeostasis. His research validated these cofactors as novel targets to treat metabolic diseases, and spurred the clinical use of natural compounds, such as resveratrol, as modulators of these cofactor pathways. Johan Auwerx was elected as a member of EMBO in 2003 and is the recipient of a dozen of international scientific prizes, including the Danone International Nutrition Award, the Oskar Minkowski Prize, and the Morgagni Gold Medal. His work is highly cited by his peers with a h-factor of over 100. He is an editorial board member of several journals, including Cell Metabolism, Molecular Systems Biology, The EMBO Journal, Journal of Cell Biology, Cell, and Science. Dr. Auwerx co-founded a handful of biotech companies, including Carex, PhytoDia, and most recently Mitobridge, and has served on several scientific advisory boards. Dr. Auwerx received both his MD and PhD in Molecular Endocrinology at the Katholieke Universiteit in Leuven, Belgium. He was a post-doctoral research fellow in the Departments of Medicine and Genetics of the University of Washington in Seattle.
