Cell Biology
Faculty and Research Interests
Jeremy Francis, PhD
Assistant Professor
Science Center 253
856-566-6050
francijs@umdnj.edu
Education
University of Auckland School of Medicine,
Auckland, New Zealand
PhD (neuroscience) 2003
Research Interest
Leukodystrophies are a subclass of neurodegenerative disorders caused by genetic abnormalities that adversely affect how the brain produces or metabolizes constituent chemicals or proteins in myelin. Myelination is a core component of synaptic integrity and is a tightly regulated, complex biological process. Identifying causative pathogenic mechanisms in leukodystrophies requires a systems based approach that enables the extrapolation of discrete genetic, molecular and biochemical observations to a whole animal phenotype. The controlled manipulation of specific pathways and processes in animal models in our laboratory aims to characterize pathogenic mechanisms with a view to identifying possible targets for therapeutic intervention. A range of analytical techniques are employed to this end, from molecular to animal behavioral analyses. Functional intervention via either gene therapy, transplantation of neural stem cells, or a combination of both forms a central component of proof of principal in vivo studies for future therapeutic development.
Transduction of neurons in the thalamus of a rat brain with an adeno-associated (AAV) viral vector containing an expression cassette for GFP. Intense fluorescence in neuronal soma can be seen at the site of injection (thal) with anterograde transport of vector resulting in GFP-positive axons throughout the internal capsule (ic). Viral vectors can deliver practically any gene of interest for functional interventions in vivo.
Transplanted GFP-transgenic cells in the subcortical white matter of a rat model of Canavan disease. GFP-positive cells indicate successful engraftment of transplant material, and co-labeling with the oligodendrocyte-specific marker APC indicates differentiation into myelin producing cells. Cell transplantation strategies can be used alone or in combination with gene therapy to develop therapeutic strategies in animal models of neurodegenerative disease
A major focus of our research is the inherited pediatric leukodystrophy Canavan disease, which is caused by inactivating mutations to the gene encoding for the oligodendrocyte specific enzyme, aspartoacylase. The sole function of aspartoacylase is the catabolism of the neuronal amino acid derivative, N-acetylaspartic acid (NAA), and loss of this function in rodents results in white matter degeneration that mirrors that seen in human patients. By characterizing the spatio-temporal regulation of the NAA metabolic cycle throughout development in the normal and aspa-null rodent brain, we hope to be able to identify key metabolic interactions between neurons and oligodendrocytes that are essential to the integrity of both cellular compartments during postnatal development.
Recent Publications
- During M.J., Cao, L., Zuzga, D.S., Francis, J.S., Fitzsimons H.L., Jiao, X., Bland, R.J., Klugmann M., Banks, W.A., Drucker, D.J., Haile, C.N. (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nature Medicine 9(9): 1173-9.
- Francis, J.S.. Dragunow, M., and During, M.J. (2004) Overexpression of ATF-3 protects rat hippocampal neurons from in vivo injection of kainic acid. Molecular Brain Research 124(2):199-203.
- Inoue, H., Osawa, I. , Murakami, T., Kimura, A., Hakamata Y., Sato, Y., Kaneko,T., Okada, T., Ozawa, K., Francis J., Leone, P., and Kobayashi, E. (2005) Development of Inbred Transgenic Strains of Rats with LacZ or GFP. Biochemical & Biophysical Research Communication.
- McPhee, S.W.J., Francis, J.S., Janson, C.G., Serikawa, T., Ong, E.O., Kolodny, E.H., Hyland, K., Young, D., During, M.J., Leone, P. (2005) Effects of AAV-2 Mediated Aspartoacylase Gene Transfer in the Tremor Rat Model of Canavan Disease. Molecular Brain Research.
- McPhee, S.W.J., Janson, C.G., Francis, J., Samulski, R.J., Freese, A., Shera, D., Leone, P. (2005) Immunological Profile of Patients Treated with AAV-2 Vectors. In Press.
- Tavazzi, B., Lazzarino, G., Leone, P., Amorini, A.M., Bellia, Janson, G.J., Di Pietro, V., Ceccarelli, L., Donizelli, S., Francis, J.S., F., Giardinia, B., (2005) Sensitive and reproducible high performance liquid chromatographic separation of N-Acetyl Aspartate, N-Acetyl Glutamate and N-Acetyl-Aspartyl Glutamate suitable for the biochemical evaluation of Canavan Disease patients. Clinical Biochemistry. 38(11): 997-1008.
- McPhee, S.W.J., Janson, C.G., Francis, J., Samulski, R.J., Freese, A., Shera, D., Leone, P. (2005) Immunological Profile of Canavan Patients Treated With AAV-2 Vectors. Journal of Gene Medicine. 8. . 8(5) 577-588 .
- Francis, J.S., McPhee, S.W.J., Olariu, A., Janson, C.G., Leone, P. A. Role for Aspartoacylase in the Regulation of BDNF and the Timing of Postnatal Oligodendrogenesis. Journal of Neuroscience Research.
In Press. - Janson CG, McPhee SWJ, Francis J.S, Shera D, Assadi M, Hurh P, Haselgrove J, Wang DJ, Bilaniuk L, Freese A, Leone P (2006). Natural history of Canavan disease revealed by serial MRI and proton magnetic resonance spectroscopy (1H-MRS). Neuropediatrics. In Press.
Professional Memberships
- American Society of Gene Therapy
- Society for Neuroscience
