My group has a long history in mTBI research, not only in characterizing behavioral and biochemical sequelae of blunt head trauma, but also in developing preclinical models of mTBI of translational relevance to support the development of new treatment strategies and drugs. In order to look for answers regarding the blast induced traumatic brain injury, we have developed a blast injury model for mice that resembles, as much as possible, the conditions on the battlefield or at a terror-attack site. As such, the outcomes of the “real-life-like” exposure to the blast in our model may vary from severe to mild brain injury under controlled conditions for each mouse.
The lab is a new multi-disciplinary molecular and cellular neurobiology lab. The lab uses state-ofthe- art single molecule live imaging techniques on neuronal cultures, as well as biochemistry, cell biology and biophysics approaches on mouse model systems to study the role of axonal transport in neurodegenerative diseases, with an initial focus on ALS.
Neuronal survival and proper function depends on cell-cell communication mediated by ligandreceptor mechanisms. During neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), there is considerable synapse/neuromuscular junction (NMJ) disruption and neuronal cell death. It is non-autonomous processes involve interactions between the neurons to its diverse extracellular microenvironments. The molecular basis for this neuronal dysfunction and death is still poorly understood. One possible reason is alterations in the nature, directed movement and spatial localization of vital extra and intracellular signals.
The long-term research goal of the lab is to understand the vital molecular communications mechanisms between the neurons and its environment. More specifically, we seek to understand the role that retrograde signaling plays in (1) neuronal survival and (2) synapse stability. We believe that our research will generate novel insights into neurodegenerative mechanisms and ultimately, provide a molecular basis for new drugs as well as delivery methods to treat a range of neurodegenerative diseases.
|2011-2015||ISF (Israel Science Foundation), The Dual Role of Dynein in GDNF Signaling|
|2011-2015||Marie Curie International Reintegration Grants (IRG), Retrogade Signaling.|
|2013-2016||Small Molecule Screen for Neuromuscular Junction Maintenance, Rosetrees Trust|
|2013-2016||E-Rare-2, European Research Projects on Rare Diseases driven by Young Investigators. Project
Coordinator. The Molecular Basis of Neurodegeneration and Muscle Atrophy in ALS. (Co-PIs: Roded Sharan, TAU; Edgar Gomes, U of Paris; Marcus Kruger, Max Planck; Del Bene Fillippo, Ins Curie; Alberto Rodendo, 12th Oct Uni Hospital Madrid)
|2013-2018||Molecular Communication Mechanism of Motor Neuron Survival and Synapse Maintenance, European Research Council (ERC) Starter Grant|
We are exploring the various mechanisms by which neural circuits encode information and support behavior, learning and memory. In addition, we are studying how the connectivity and activity of such circuits and neural networks are affected by molecular mechanisms underlying brain disorders. We use a multidisciplinary approach, with the Drosophila olfaction system as our model system. Our studies incorporate in vivo whole cell patch recordings, in vivo functional imaging, behavior experiments, molecular biology, mathematical modelling and genetics.
Projects in the lab include:
- Intensity and identity coding in a multidimensional sensory system – the Drosophila olfactory system.
- Neuropeptidergic modulation of olfaction and its effect on odour perception.
- The role of deregulated channel proteins and altered neuronal function in Frontotemporal Dementia.
- A novel multifaceted approach to study the mechanisms underlying the effects of human genes associated with schizophrenia using Drosophila.
Dr. Yuval Nir, Ph.D.
Department of Physiology and Pharmacology
Sleep is a universal behavior that is present across the animal kingdom. We spend a third of our lives sleeping, disconnected from the world around us. Our sleep is closely regulated so that when we are sleep-deprived, we ultimately compensate with longer, deeper sleep. Sleep helps our cognitive performance, promoting learning and memory consolidation. Lack of sleep immediately affects our cognition, mood, and health. All this suggests that sleep is essential, but what exactly is it about brain activity during sleep that is so crucial for restoring our normal cognition?
Sleep also involves dramatic changes to our perceptual awareness. Sometimes our consciousness fades altogether while at other times we experience vivid dreams. Although our brain continues to be active, we are mostly disconnected from sensory signals such as sounds, which would otherwise be perceived, trigger plasticity and result in behavior. How does the internal state of brain activity during sleep affect brain responsiveness and perceptual awareness?
Our goal is to understand how sleep relates to cognition and perception. Our research is guided by a belief that such studies require a combination of human and animal models. We therefore use multiple experimental techniques, focusing on the strengths of each setup to investigate the same key questions synergistically. Animal models are used to investigate underlying mechanisms, by performing detailed recordings of electrical activity and by manipulating neuronal activity with optogenetic, electrical and sensory stimulation. Human studies are carried out for careful investigation of cognitive factors and for studying large-scale brain activity (with fMRI, EEG, recordings in neurosurgical patients, and behavioral tests).
|2014 – 2018||
EU Marie Curie Career Integration Grant (CIG)
|2013 – 2018||I-CORE Cognitive Neuroscience|
Prof. Talma Hendler, M.D., Ph.D.
Department of Physiology and Pharmacology
Department of Psychiatry
Investigating brain mechanisms underlie generation and regulation of the human emotional experience, in healthy and pathological states. The research is based on measuring indices of brain structure and functional dynamics via MRI (functional-MRI, DTI and Volumetric-MRI) and separate or simultaneous recording of electrical signals (scalp-EEG and intracranial-EEG). The characterization of individual brain response is based on correlating neural activity and connectivity with behavioral and physiological measurements of emotionality (e.g. heart rate, hormone secretion, genetic expression, skin conductance, eye movements and verbal output). Induction of emotional states is achieved via film and music media, inter-personal interactions, and interactive social games. Regulation of emotions is modulated via on-line feedback protocols from brain signals in a closed loop set-up (i.e. NeuroFeedback).
The lab is also involved in studies aim to advance translation while focusing on neural markers of vulnerability and recovery with regard to post traumatic disorders (e.g. anxiety and depression), developmental disorders (e.g. schizophrenia and personality) and neurodegenerative disorders (e.g. Parkinson disease). An essential part of this aspect of our work is the development of advanced new tools for acquiring and analyzing whole brain neural measurements; including applying multi-scale mapping for capturing dynamics of brain networks.
Our research is characterized by a multi-level approach to the study of brain function, behavior, memory and drug discovery, from molecules to cures. Targeting autism, schizophrenia as well as Alzheimer’s disease and related neurodegeneration and utilizing a multidisciplinary approach, our group investigates different aspects of neuronal plasticity and nerve cell protection, at the molecular, cellular and system level.
A major focus in the laboratory is on nerve structure and transport mechanisms. We have discovered novel families of proteins associated with cross talk among nerve cells and their support cells, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotetive proteins (ADNPs, with ADNP being a major gene mutated in autism). Small ADNF and ADNP derivatives are in clinical development. The lead compound, davunetide is planned for an advanced Phase II clinical trial with the biotech industry.
Davunetide has previously shown efficacy in several Phase II clinical trials (i.e. in patients suffering from mild cognitive impairment, preceding Alzheimer’s disease and in schizophrenia patients, protecting activities of daily living).
Our research is focused on the molecular mechanisms regulating the protein kinase GSK-3 and their implications in human disease. GSK-3 is a central player in diabetes, neurodegenerative and psychiatric disorders, and recently emerged as a promising drug discovery target. We propose that inhibition of GSK-3 should produce therapeutic benefits in treating these disorders. We develop selective substrate competitive GSK-3 inhibitors and evaluate their efficacy and therapeutic effects in relevant in vitro and in vivo systems. So far we could show that our leading compound inhibitors had therapeutic efficacy in CNS disorders models for Alzheimer’s disease, mood disorders, and multiple sclerosis.
In recent work we identified the lysosome as a GSK-3 target. This implicated GSK-3 as a key player in protein degradation pathways, particularly autophagy ad endocytosis. Research methods combine cell biology, molecular biology and biochemistry disciplines together with bioinformatics and computational biology.
Prof. Ruth Ashery-Padan, Ph.D.
Department of Human Molecular Genetics and Biochemistry
We study the gene networks that transform the embryonic cells into a complex, differentiated organ. We focus on exploring this question by studying the process of eye development as a model for organogenesis. We apply cutting-edge technologies including mouse genetic tools (Cre/loxP), molecular biology, and microarray analysis to identify and functionally characterize genes that regulate the development of the eye in mammals. Understanding the normal developmental regulation of the different eye structures is essential for understanding visual disorders and designing treatments for ocular phenotypes including retinal degeneration, glaucoma and cataracts, all of which are leading causes of blindness.
Roles for microRNA in RPE differentiation, Morasha, Israel Science Foundation
|2012-2015||Roles for Pax6 in neurons of the olfactory bulb, midbrain and retina, German Israeli Foundation (Co-PI with Magdalena Goetz).|
Breast cancer is the most common malignant disease in western women. In the majority of cases the cause of death in cancer patients is not the primary tumors, but complications derived from metastases at distant sites. The met proto-oncogene product (Met - a receptor tyrosine kinase) and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), mediate cell motility and proliferation in vitro and tumorigenicity, angiogenesis and metastasis in vivo. Mimp/Mtch2, a mitochondrial carrier homologue cloned in our lab, is induced by Met-HGF/SF signaling and is involved in metabolic and bioenergetic processes. We have previously shown that activation of Met by HGF/SF induces an increase in tumor blood volume in a dose-dependent manner. Mimp/Mtch2 reduces cells proliferation in vitro and tumor growth in vivo. Several anti-Met targeted therapies are in development and some have entered phase III clinical trials.
The goal of our studies is to further understand the role of Met-Mimp/Mtch2 in cancer progression and metastasis, and to develop modalities for personalizing targeted Met therapy. Fluorescent tagged–Met proteins were used to study Met mitogenic effect on cells. Met induced cell motility is mediated by the formation of membrane structures such as ruffles, pseudopodia and blebs. Over expression of GFP-Met WT results in its constitutive activation, cell rounding and detachment, and dynamic nonapoptotic membrane blebbing. Bleb retraction results in numerous membrane microspikes where CFP-Met WT, YFP-actin and membrane markers accumulate.
Expression of Dominant-Negative (DN) YFP-Met alone did not induce any membrane blebbing, and co-expression of CFP-Met WT and YFP-Met DN significantly reduces membrane blebbing. Using confocal based molecular imaging we also show that Mimp/Mtch2 reduces the levels of reactive oxygen species ROS and prevents the HGF/SF induced increase in ROS. Mimp/Mtch2 also reduces the polarization of the mitochondrial membrane potential.
Prof. Yosef Shiloh, Ph.D.
Department of Human Molecular Genetics and Biochemistry
Our laboratory investigates the cellular DNA damage response. This research stems from our interest in the human genetic disorder ataxia-telangiectasia (A-T), in which a central axis of the DNA damage response is missing.
Genetic defects in the DNA damage response lead to genomic instability syndromes, which usually include tissue degeneration, cancer predisposition, and sensitivity to specific DNA damaging agents. A prototype genomic instability syndrome is A-T. The disease is characterized by neuronal degeneration, immunodeficiency, chromosomal instability, sensitivity to ionizing radiation, and cancer predisposition.
Our lab has been investigating A-T since its establishment in 1985. In 1995, after 8 years of intensive work, we identified the gene that is defective (mutated) in A-T patients and called it ATM (A-T, Mutated). We went on to study the activity of its product, the ATM protein, which turned out to be an enzyme with an activity alled “protein kinase." Our current research is aimed at a broader understanding of the ATM-mediated DNA damage response. Particular attention is paid to the molecular and physiological basis of A-T, which may eventually lead to new treatment modalities for the disease. We investigate this system with cell biology methods, gene targeting in mice, and systems biology strategies including high-throughput screens, advanced proteomics and bioinformatics. A study is underway aimed at understanding the DNA damage response in the part of the brain called the cerebellum, which is badly damaged in A-T patients. Another project is searching for a drug treatment for A-T patients based on our recent understanding of the disease.
Prof. Ronit Satchi-Fainaro, Ph.D.
Department of Physiology and Pharmacology
Our research interests include investigations relating to tumor biology, tumor dormancy, mechanism of action of angiogenesis inhibitors, self-assembly of polymeric architectures and novel approaches to target cancer. Throughout, we have maintained an interest in understanding the biological rationale for the design of polymer therapeutics suitable for transfer into clinical testing.
Our primary interests are the molecular basis of tumor angiogenesis and the rational design of polymer therapeutics. Our research includes identification and characterization of genes and microRNAs associated with the switch from a dormant avascular tumor phenotype to a fast-growing angiogenic tumor in human cancers and their corresponding mouse models. We focus on the design and characterization of novel drug delivery platforms, including dendrimers and hyperbranched polymer–based nanoparticles, and the design of highly-selective targeting molecules integrating biology, chemistry, protein engineering, computational approaches, material sciences
and nanotechnology to selectively guide drugs into pathological sites.
Our vision is that novel approaches to target anticancer, anti-angiogenic drugs, miRNA and siRNAs to endothelial and tumor cells to potentially treat angiogenesis-dependent diseases could transform cancer into a chronicallymanageable disease. Research methods used include sequencing, gene cloning, quantitative RTPCR, immunofluorescence, cell culture, scanning electron microscopy, mass spectrometry, NMR, HPLC, in situ hybridization, bioinformatics, polymer chemistry, molecular imaging, angiogenesis assays, animal models of cancer (human xenografts in mice, syngeneic and transgenic mice models),
pharmacokinetics and pharmacodynamics.