Sandra Rieger

Education

Ph.D. Helmholtz Center Munich, Germany 2008

Biosketch

Dr. Rieger was born and raised in Germany. She obtained her Ph.D. in Developmental Genetics from the Helmholtz Center in Munich where she studied the role of cell-cell adhesion factors in granule precursor cell migration during zebrafish cerebellar development. She was the first to demonstrate the characteristics and dynamics of N-cadherin in migrating granule precursor cells using time-lapse imaging. She further studied the role of polysialylated neural cell adhesion molecule (PSA-NCAM) during migration and discovered its prominent expression in neurogenic zones of the adult zebrafish brain, as well as a function in guiding migrating cerebellar precursor cells from the rhombic lip to deeper brain regions during early cerebellar development. Dr. Rieger completed her postdoctoral training at the University of California Los Angeles where she explored neuro-epithelial interactions during cutaneous wound repair. She utilized the zebrafish as a model system to study the dynamic processes of sensory axon regeneration and wound repair in vivo. She identified the small reactive oxygen species hydrogen peroxide as a critical factor in injury-induced cutaneous sensory axon regeneration. Following her postdoctoral training, Dr. Rieger was appointed as assistant professor at MDI Biological Laboratory, a non-profit research organization focusing on regenerative and aging biology. Her lab continues to study the role of hydrogen peroxide and cutaneous sensory axons in wound repair. Dr. Rieger is also interested in the development of models and therapies for neurodegenerative disorders involving cutaneous sensory axons. Her lab has established a zebrafish in vivo model of paclitaxel-induced peripheral neuropathy, a common side effect of chemotherapy, for which no know cures are available. This zebrafish model has aided in the identification of lead compounds, two of which are currently being investigated in mice and may be advanced to clinical studies.

Research Interests

Tissue repair is an intricate process, which requires the coordinated interactions between various cell types in the wound. The small reactive oxygen species hydrogen peroxide (H2O2) plays an important role in wound repair by functioning as a pleiotropic signaling molecule to attract leukocytes toward the site of injury, by promoting angiogenesis, and by stimulating cutaneous sensory axon regeneration (Rieger & Sagasti, PLoS Biology 2011). We are particularly interested in the mechanisms of H2O2 signaling during wound repair. In addition, we have developed a zebrafish model for studying mechanisms of paclitaxel-induced peripheral neuropathy in the living animal using in vivo imaging. Paclitaxel is a chemotherapeutic agent that is widely used in the treatment of breast, ovarian and lung cancer. It has been shown that up to 97% of patients treated with paclitaxel develop symptoms such as numbness, tingling and pain. While many patients recover, those that are most severely affected (~30%) must terminate chemotherapy or reduce the dose, which deprives them of the full benefits of cancer treatment. The mechanisms underlying this condition are unclear and hence there are no effective treatments available. We hope that our research will contribute to the development of therapeutics. By utilizing the knowledge gained from axon regeneration studies, we have been able to identify a new drug target that shows promising results in the treatment of paclitaxel-induced peripheral neuropathy in zebrafish.

Ongoing Lab Projects

Project 1: Define the molecular mechanisms that promote injury-induced cutaneous axon regeneration

Injury-induced cutaneous axon regeneration is conserved among vertebrates but despite this conservation, we do not yet fully understand the basic mechanisms underlying this process. We are exploring in particular the role of H2O2 and its downstream targets in promoting cutaneous axon repair. We previously showed that cutaneous axon regeneration critically depends on H2O2 that is released from keratinocytes after injury. Identifying and analyzing the function of H2O2 and its targets will be critical for developing strategies that promote axon growth under pathological conditions, such as peripheral neuropathy disorders. We are utilizing genetically accessible and optically clear zebrafish larvae to assess the interactions between cutaneous axons and wound keratinocytes in live animals. We have already identified several interesting H2O2-dependent molecules using RNA sequencing and begun to vigorously dissect the molecular mechanisms leading to cutaneous axon regeneration. Our studies point to a parallel signaling function of H2O2 in keratinocytes and somatosensory neurons, both of which are essential for axon regeneration.

Project 2: Delineate the role of epidermis in paclitaxel-induced peripheral neuropathy

We developed a zebrafish in vivo model to analyze mechanisms of paclitaxel–induced axon degeneration and impaired regeneration in live zebrafish (Lisse et al., PNAS accepted). This model revealed that the epidermis undergoes rapid phenotypic changes upon paclitaxel-treatment prior to the onset of axon degeneration. These changes correlate with upregulation of the collagen-degrading matrix metalloproteinase, MMP-13, in epidermal keratinocytes. Excitingly, co-administration of paclitaxel and two MMP-13 inhibitory compounds show significant beneficial effects (patent pending), suggesting that increased MMP-13 activity and matrix degradation in the epidermis underlies paclitaxel neurotoxicity. A common view is that paclitaxel causes neurotoxicity by axon-specific microtubule stabilization leading to microtubule transport defects and mitochondrial damage. We argue that not axons but rather keratinocytes are the primary targets of paclitaxel in the etiology of paclitaxel-induced peripheral neuropathy. We are currently exploring this idea. We are also collaborating with investigators at the Mayo Clinic, Rochester MN to further explore the role of MMP-13 in human paclitaxel-treated patients.

Project 3: Identify sensory axon-dependent wound repair mechanisms

Successful wound repair is dependent on axonal reinnervation. Evidence from denervation models suggest that loss of cutaneous axons, either experimentally in denervation models or due to disease, such as diabetes, delays wound healing and may lead to chronic wound formation. Keratinocyte migration is an essential aspect of wound closure and we have established an in vivo zebrafish epithelial wound healing model that allows us to determine the role of sensory axons in wound repair using time-lapse imaging.

 

Selected Publications

  • O’Brien GS, Rieger S, Wang F, Smolen GA, Gonzalez RE, Buchanan J and Sagasti A: Coordinate development of skin cells and cutaneous sensory axons in zebrafish. J Comp Neurol. 2011 Oct 20. doi: 10.1002/cne.22791. [Epub ahead of print]
  • Rieger S, Sagasti A Hydrogen Peroxide Promotes Injury-Induced Peripheral Sensory Axon Regeneration in the Zebrafish Skin. PLoS Biol 9 (5) 2011.
  • Rieger S, Wang F, Sagasti A: Zebrafish time-lapse imaging during nervous system development. Genesis. Feb 8, 2011.
  • Rieger S, Senghaas N, Walch A, Köster RW: Cadherin-2 Controls Directional Chain Migration of Cerebellar Granule Neurons. PLoS Biol. Nov;7 (11) 2009 (Evaluated by Faculty of 1000)
  • O’Brien GS, Rieger S, Martin SM, Cavanaugh AM, Portera-Cailliau C, Sagasti A: Two-photon axotomy and time-lapse confocal imaging in live zebrafish embryos. Journal of Visualized Experiments Vol. 24, 2009
  • Rieger S, Volkmann K, Köster RW: Polysialyltransferase expression is linked to neuronal migration in the developing and adult zebrafish Developmental Dynamics, Vol. 237 (1), 2008
  • Volkmann K, Rieger S, Barbaryka A, Köster RW: The zebrafish cerebellar rhombic lip is spatially patterned in producing granule cell populations of different functional compartments. Developmental Biology, Vol. 313(1), 2008
  • Rieger S & Köster RW: Preparation of Zebrafish Embryos for Transmission Electron Microscopy, CSH Protocols; 2007; doi:10.1101/pdb.prot4772
  • Rieger S, Kulkarni RP, Darcy D, Fraser SE, Köster RW: Quantum dots are powerful multipurpose vital labeling agents in zebrafish embryos. Developmental Dynamics Special Edition, Vol. 234(3), 2005 (Evaluated by Faculty of 1000)
  • Cover Image of Developmental Dynamics Special Edition: Developmental Neurobiology, November 2005
  • Beckers J, Herrmann F, Rieger S, Drobyshev AL, Horsch M, Hrabe de Angelis M, Seliger B: Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis. International Journal of Cancer, Vol. 114(4) 2005
  • Horr B, Borck H, Jones M, Lebert A, Rieger S, Diel F: Pyrethroids do not show relevant ex vivo histamine releasing potency in human basophils. Inflammation Research, 2003 Vol. 52 Suppl. 1

Grants

  • 2011 to 2014 — P20RR16463 Hand) from NIH/NCRR
  • 2011 to 2013 — W81XWH-BAA-11-1 (Strange) from USAMRAA

Dissertation Students

Anthony Cirrincione

Matthew Scott