ד”ר ניבה רוסק-בלום
Early macrophages colonization of the brain, their transition to fully differentiated microglia, their effect on neighboring neurons development and behavior and the genetic pathways underlying these processes.
Recent studies on microglial origin indicate that these cells arise early during development from progenitors in the embryonic yolk sac that seed the brain parenchyma and, remarkably, appear to persist there into adulthood. We use the zebrafish, transparent vertebrate whose immunological features resembles ours, to understand the origin, differentiation, and homeostasis, of microglia cells which is expected to provide new insights into their roles in health and disease. We exploit fate mapping procedures to better refine primitive macrophages invasion and colonization of the brain. To define the differentiation process and to be able to find unique markers for these cells, genes that define microglial differentiation are being characterized. The exact role and timing of distinct signaling pathways involved in this process, such as TGF-β, are examined.
The immune perspective of neurodegenerative disorders in the zebrafish brain.
The role of microglia and circulating macrophages in neurodegenerative disorders in a zebrafish model as a mean to get further insights to basic unresolved questions in neuroimmunology and to establish an infrastructure required for the initial screen of potential therapeutic agents.
The impact of inflammatory responses is rapidly assuming major roles in ischemic stroke and neurodegenerative pathologies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). In recent years, progress has been made in developing new therapies that target the immune system or treatments that use components of the immune system as therapeutic agents.
As part of this inflammatory response in the brain, microglia, yolk-sac -derived macrophages of the CNS, undergo chronic activation promoting both beneficial and toxic effects upon the neuronal network. A great effort is thus now being established in elucidating the process of cell recruitment to the brain and signaling pathways underlying their activation throughout the inflammatory response to neurodegenerative pathologies.
We use the zebrafish, a leading model organism for developmental biology and human disease, as a vertebrate genetic model to study immune mechanisms in the progression of ischemic stroke and ALS. More specifically, we utilize established transgenic lines to track the migration and activation of microglia cells within the healthy vs diseased brain using state-of-the-art live cell imaging and image analysis. We analyze microglia role in synapse turnover and neuronal activity in SOD1 G93R model for ALS and in zebrafish model of ischemic stroke. Furthermore, to establish the signaling pathways underlying the immune response in the brain, genetic modifications are performed to determine the effect of distinct genes on the ischemic and neurodegenerative processes.
A high-throughput screening (HTS) system of zebrafish for the evaluation of potential ALS therapeutics.
Amyotrophic lateral sclerosis (ALS) is an incurable, progressive neurodegenerative disease affecting motor neurons. For rapid screening of potential drugs that will slow/inhibit the progression of the disease, a high-throughput system that will faithfully recapitulate the disease phenotype is required. Zebrafish models for ALS were generated and study results showed that they can complement existing mammal models. Transgenic zebrafish for the major ALS-linked gene superoxide dismutase 1 (SOD1), is utilized in our laboratory. We have established a high throughput screening platform that involves both behavioral and morphological aspects. Drug candidates are added to the water containing the embryos at different days before analysis. We screen libraries of compounds implicated in proper neural development and neuro-protection to be used potentially as a treatment for ALS mutations-carriers.
- Soll M†, Goldshtein H†, Rotkopf R, Russek-Blum N*, Gross Z*. A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS. Antioxidants. 10 (6), 827, 2021. († equally contributing authors; * Corresponding authors). COVER STORY: https://www.mdpi.com/2076-3921/10/6
- Goldshtein H, Muhire A, Petel Legare V, Pushett A, Rotkopf R, Shefner JM, Peterson RT, Armstrong GAB, Russek‐Blum N. Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 7(10):1883-1897, 2020.
- Russek-Blum N and Monsonego A. Morphological aspects of microglia in development, aging and disease.
Andreasson KI*, Bachstetter AD, Colonna M*, Ginhoux F*, Holmes C*, Lamb B*, Landreth G*, Lee DC*, Low D, Lynch MA*, Monsonego A*, O’Banion MK*, Pekny M*, Puschmann T, Russek-Blum N*, Sandusky LA, Selenica MB, Takata K, Teeling J, Town T*, Van Eldik LJ*.Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. Jun 1. 2016. (*equally contributing authors).
- Russek-Blum N, Nabel-Rosen H, Levkowitz G. Two-Photon- Based Photoactivation in Live Zebrafish Embryos. J Vis Exp. Dec 24;(46), 2010.
- Russek-Blum N, Nabel-Rosen H, Levkowitz G. High resolution fate map of the zebrafish diencephalon. Dev Dyn. 238(7):1827-35, 2009.
- Russek-Blum N, Gutnick A, Nabel-Rosen H, Blechman J, Staudt N, Dorsky R.I., Houart C, Levkowitz G. Dopaminergic neuronal cluster size is determined during early forebrain patterning. Development135(20):3401-13, 2008.
- Dekel I, Russek N, Jones T, Mortin M.A., Katzav S. Identification of the Drosophila melanogaster homologue of the mammalian signal transducer protein, Vav. FEBS Lett, 472:99-104, 2000.
- Groysman M, Shifrin C, Russek N, Katzav S. Vav, a GDP/GTP nucleotide exchange factor interacts with Ly-GDI, a GDP/GTP dissociation inhibitor protein. FEBS Lett, 467:75-80, 2000.