Genetic dissection of disease mechanisms

Our basic approach is to genetically manipulate and change genes in mice and to determine the effects of these mutations in development of the whole organism and in diseases. From these mutations we are trying to establish basic principles of development and basic mechanisms of disease pathogenesis.

  • First evidence of complete cardiac regeneration in humans.

    Each year, 17 million people around the world die of cardiovascular diseases, 2 million of them in the EU alone (WHO). Even though medical care for cardiac patients has improved tremendously and the immediate fatality rate has dropped, most patients still face permanent damage leading to chronic heart failure. During a heart attack, cardiac muscle cells die and are replaced by scar tissue. But scar tissue cannot pump, which leads to limitations in cardiac function and a weakening of the heart muscle. So far, heart muscle cells lost in adults cannot be efficiently regenerated despite innovative approaches such as stem cell therapy. Pioneering experiments demonstrated that fish can completely regenerate the heart following resection of the heart apex, spurning a plethora of studies using fish as a model organism.

    Our group and Olson’s group have recently reported complete morphologic and functional cardiac repair in newborn mice following severe myocardial infarction. Two key issues remain to translate findings in model organisms to future therapies in humans: what is the mechanism and can cardiac regeneration indeed occur in newborn humans? We now report the case of a newborn child suffering from a severe myocardial infarction due to coronary artery occlusion. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography (Figure 1). Remarkably, within weeks after the initial ischemic insult, we observed functional cardiac recovery, which translated into long-term normal heart function. These data indicate that, similar to neonatal rodents, newborn humans have the intrinsic capacity to repair myocardial damage and completely recover cardiac function (Haubner et al. Circ. Research 2015).

    Identification of a critical transcriptional regulator of pain perception.

    Chronic and acute pain affects millions of people worldwide producing an enormous financial and quality of life burden. The detection of noxious or damaging stimuli (nociception) is an ancient process that alerts living organisms to environmental dangers. Harmful stimuli activate receptors on specific sensory neurons called nociceptors, which mediate information transfer via the spinal cord to higher order processing centers resulting in protective behaviors and awareness of pain. Pain perception is essential for an animal to thrive, and human patients that cannot sense pain, such as patients with hereditary sensory and autonomic neuropathy (HSAN), die prematurely due to multiple injuries.

    PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. We show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution. Expression of wild-type human PRDM12 in Xenopus induced the expression of sensory neuronal markers, which was reduced using various human PRDM12 mutants. In Drosophila, we identified Hamlet as the functional PRDM12 homologue that controls nociceptive behavior in sensory neurons. Furthermore, expression analysis of human patient fibroblasts with PRDM12 mutations uncovered possible downstream target genes. Knockdown of several of these target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE) in Drosophila sensory neurons resulted in altered cellular morphology and impaired nociception. These data show that PRDM12 and its functional fly homologue Hamlet are evolutionary conserved master regulators of sensory neuronal specification and play a critical role in pain perception. Our data also uncover novel pathways in multiple species that regulate evolutionary conserved nociception (Nagy et al. Cell Cycle 2015).


    Figure 1 (click to view legend)

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