Our laboratory is interested in mechanisms that generate and maintain neuronal identity. Much of our work is concentrated on molecular mechanisms that regulate gene expression. The long-term goal of the laboratory is to establish collaborations that enable translation of this basic mechanistic information into novel treatments for neurological disease.
Phenotype specification andcellular organization in regenerating neural circuits
This project focuses onhow phenotypes of neurons generated in the adult subventricular zone (SVZ) are specified and how these neurons integrate into matureolfactory bulb circuits. The olfactory bulb is the initial processing center for odorant sensory information, and mitral and tufted projection neurons within the bulb relay odorant information from olfactory receptor neurons in the olfactory epithelium to cortical regions, such as the piriform cortex. This relay is modulated by interneurons in the olfactory bulb. Whereas mitral and tufted projection neurons are generated during embryonic development, most of theolfactory bulb interneuron population is generated by progenitors produced in the post-natal SVZ. In adult rodents, olfactory bulb interneuronsturn over and are regenerated by progenitors produced by neural stem cells in the SVZ. The olfactory bulb interneuron population is not homogenous, however, and there are several distinct interneuron sub-types based on the co-expressed of other neurotransmitters, neuroactive peptides and calcium binding proteins. Olfactory bulb interneurons also make different synaptic connections depending on the layer in which they reside. Thus, the SVZ and olfactory bulbprovides an ideal system to study fundamentalquestions about gene transcription regulatory mechanisms that direct phenotype specification and circuit organization.
Our laboratory is currently interested in understanding how the GABAergic phenotype that is expressed by nearly all olfactory bulb interneurons is specified. We are also investigating how specific sub-types of olfactory bulb GABAergic interneurons are specified, such as those that also co-express dopamine. Furthermore, the laboratory is addressing how laminar organizationin the interneuron population is established. For example, how are migrating adult-born progenitors directed to either the glomerular or granule cells layers? Finally, the laboratory is also interested in understanding how disease or injury alters these specification and organizing mechanisms.
Small molecule manipulation of gene expression
Nucleic acid secondary structures, such as G-quadruplexes and i-motifs, are emerging as important regulators of gene expression in the nervous system. Our laboratory has recently shown that nucleic acid secondary structures are instrumental in regulating the expression of tyrosine hyrdoxylase and glutamic acid decarboxylase 1. This research project builds on these recent findings and explores the potential of using small molecules to modulate nucleic acid secondary structure stability in order to manipulate gene expression in either mature neurons or neural progenitors. There are several directions that we are pursuing with this strategy, including:
- providing neuroprotection from oxidative stress resulting from either stroke or neurodegeneration
- altering cell fate in differentiating neural progenitors
- modifying expression levels of specific genes for therapeutic benefit, such as pain alleviation
The studies in this projectwill provide new and fundamental insights into the role that nucleic acid secondary structure has in regulating gene expression in the nervous system. Furthermore, these studies will address whether nucleic acid secondary structures are effective molecular targets for treating neurological diseases that offer exciting opportunities for developing novel pharmacological therapies.
Adult neural stem cells as a source of replacement neurons for Parkinson’s Disease
Stem cells are an ideal source of neuronsto make cell replacement therapy a practical treatment strategy for Parkinson’s Disease.Adult SVZ neural stem cells have several advantageous propertiesfor therapeutic application when compared to either embryonic or induced pluripotent stem cells. These include:
- being already committed to a neural lineage
- not having the tumor-forming potential of either embryonic or induced pluripotent stem cells
- being a potential source of autologous replacement neurons since they can be endoscopically harvested from the lateral ventricle wall by penetrating non-eloquent parts of the brain
This project aims to define culture conditions that maximize the number of dopaminergic neurons progenitors generated from adult mouse SVZ neural stem cells.A second aim is to demonstrate that dopaminergic neurons can be efficiently generated from human adult SVZ NSCs and that these dopaminergic progenitors can provide functional relief in a PD rodent model system.Together, these studies will establish whether adult SVZ neural stem cellscan produce dopaminergic neurons suitable for cell replacement therapy to treat Parkinson’s Disease.