Ernesto Bongarzone

    Email Address:
    College: Medicine Department: Anatomy and Cell Biology
    Title: Associate Professor
    Office: COMRB 9073 Phone: 66894
    Participating in the Chancellor’s Undergraduate Research Awards program: Yes

    Research Interest:
    I have a long-standing interest in the neurobiology of myelination. Myelin is the sheath of apposed membranes that wraps and electrically insulates axons of the central and peripheral nervous systems. Numerous conditions including multiple sclerosis, genetic leukodystrophies, neurodegenerative pathologies, aging and intoxications increase myelin vulnerability, leading to disease, which remains largely incurable. The long-term goal of my research program is to translate our detailed understanding of pathogenic mechanisms of disease into rationalized therapies to cure demyelination. In particular, my laboratory is interested on:

    1) Synergy therapies for genetic leukodystrophies. Demyelinating lysosomal storage orphan diseases such as Krabbe disease (deficiency of Galactosylceramidase) or metachromatic disease (MLD, deficiency of arylsulfatase A) are currently very difficult to treat. Early therapeutic studies performed on mouse models for Krabbe disease and MLD indicated the relevance that the disease phenotype exerts on the outcome of a therapy. Mutant mice with a milder neurological phenotype such as the MLD mice responded positively to gene and cell therapies (Luca et al., 2005; Givogri et al., 2006; Givogri et al., 2008). In contrast, these therapies failed in the severe twitcher mouse, a model for Krabbe disease (Dolcetta et al., 2004; Galbiati et al., 2005; Galbiati et al., 2009). Further experimentation from my laboratory demonstrated the complexity of Krabbe disease, becoming evident that this leukodystrophy is compounded with various additional pathogenic mechanisms, most of them driven by the toxicity of psychosine (the material that is stored in Krabbe disease). With federal and private funding, we are investigating an array of basic cell biology questions including how psychosine affects membrane biogenesis and lipid rafts, axonal cytoskeleton, vesicular axonal transport and neuromuscular junction (White et al., 2009; White et al., 2010; Cantuti et al., 2011, 2012, 2013; Smith et al., 2012; Smith et al., 2014). With these findings, it became obvious that single therapies would fail to cure Krabbe disease. Departing from a better understanding of Krabbe’s pathogenesis, my lab is interested in determining the benefits of combining gene therapy, cell therapy and targeted neuropharmacology. We are interested in determining the best synergic therapies for Krabbe disease resulting from combining different routes of delivery, vectors (adeno-associated viral or lentiviral vectors), donor cells (bone marrow, neural stem cells) and drugs (inhibitors for kinases, phosphatases and neuroprotectors). As a result from this effort, my lab is heavily involved with the Krabbe Translational Research Network, a private consortium grouping most of the labs working on Krabbe disease in US. Teamwork with components of this network have consolidated the design and current discussion with federal authorities for a phase I clinical trial for Krabbe disease.

    2) Mechanisms of axonopathy in myelin diseases. It is clear that neuropathology in most myelin diseases involves not only damage to myelin and oligodendrocytes but also to axons and neurons. Our findings in genetic leukodystrophies are examples of how relevant these two neuropathological aspects are at the moment of formulating a therapy. However, the mechanisms of axonal/neuronal degeneration during demyelination in other important myelin diseases such as multiple sclerosis remain vastly uncharacterized. This gap of information feeds our current interest in studying the regulation of fast axonal transport during myelin disease. Vesicular transport is a physiological process vital for the survival of the axon and the neuron. Axons are very long structures connecting the neuronal soma to their targets, which may reside several centimeters away. Even small reductions of vesicular transport efficiency could be detrimental and cause neuronal disease. For example, the activity of neuromuscular junctions relies upon nerve connections with very long axons, sometimes a meter or more long. If the transport and/or release of synaptic vesicles containing acetylcholine is reduced only by 5-10%, this translates in slower muscle responses to many muscle fibers, impacting on the efficiency of muscle contraction for the patient, a feature present in all myelin diseases. With funding support from NIH, we are studying how pharmacological intervention may protect and ameliorate neurodegeneration in some myelin diseases. Using animal models we have identified various signaling pathways that appear to directly affect axonal transport of vesicles and the stability of the neuron-axon-target axis (Cantuti et al., 2011; Cantuti et al., 2012; Cantuti et al., 2013). My interest is to expand our results to other relevant signaling pathways and diseases and determine how transport deregulation occurs during demyelination and responds to remyelination. Ultimately, these studies will formulate new synergic therapies combining metabolic correction and neuropharmacology to preserve the health of the affected neurons in myelin diseases.

    3) Cellular and molecular mechanisms regulating remyelination in disease and aging. My interest to positively treat myelin diseases is complemented with work on remyelination. The demonstration of de novo generation of neural cells (neurogliogenesis) in the adult brain and the presence of adult oligodendrocyte progenitors throughout the CNS provide a unique possibility to study the in vivo behavior and responses of these cells to disease and to identify molecular targets for therapy. Currently, we are characterizing the response of endogenous brain progenitors to viral infection. Our studies use the Theiler’s murine encephalomyelitis virus and have identified virus-mediated signaling pathways affecting oligodendrocytes differently than other neural cells such as astrocytes or neurons (Hebert et al., in submission). In addition, specific micro-RNA responses apparently involved in decreased remyelination have been identified. We are interested in evaluating potential benefits of interfering with micro-RNAs to enhance myelin repair.

    Minimum time commitment in hours per week: 15

    Qualifications of a Student:
    Priority is given primarily to Biology/Chemistry majors with top GPAs (>3.5). Freshman and sophomores pursuing Medical/Graduate school are particularly encouraged to apply. Prior research experience is an advantage but not necessary. The applicant should be able to quickly learn and master new techniques, have excellent communication and team-work skills, be mature, reliable and highly organized with lab notes, working hours and general activities within the lab. Candidate must be able to devote at least 15 hours/week in chunks of 3-5 hours.

    Brief Summary of what is expected from the student:
    Candidates shall expect a social tranquil and highly interactive lab environment. Students will be exposed to senior researchers who are prone to share their talents and knowledge. Students are expected to learn from them, being able to follow protocols and techniques with precision, developing multi-tasking and problem solving skills. Open communication is expected at all times regarding time-off, exams, vacations, etc. Lab time is expected to be devoted to lab activities only. Students should expect to start a training period where they will be under the supervision of a senior technician to learn general lab duties and techniques. After this period and with evidence of gained precision, commitment and trouble-shooting skills, students are expected to become fully embedded in a particular project under the direction of a project leader. We seek students who may remain during junior and senior years fully engaged in an Honors study.

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