The dynamics and logic of neuroglial interactions in neurodegenerative pathologies
The overall goal of our laboratory is to uncover rules that govern the complex interactions between all brain cell types in their unperturbed in vivo microenvironment and to determine how these dynamic cell-cell interactions are disrupted in a variety of disease states. We utilize high-resolution cellular imaging in vivo and fixed tissues of single cells and small clusters of interacting cells combined with novel optical sensors of cellular physiology, optogenetics, chemogenetics, genome editing techniques and methods that we develop for improving the capacity to visualize and manipulate individual cells in their native environment. Our approach tends to be exploratory and hypothesis generating and thus, our results can take us in different directions such that projects in the lab can have a neuronal, glial or vascular focus. Finally, discoveries derived from these investigative strategies inspire our translational neuroscience program aimed at neurodegenerative conditions.
Extensive Research Description
Cellular and molecular mechanisms of neurodegeneration: Neurodegenerative diseases such as Alzheimer’s are the result of complex and multicellular age-related cellular processes that disrupt normal cellular functions and neuroglial interactions. This eventually results in disruption of intercellular communication, loss of synapses and cell death. We are interested in various components of neurodegeneration including:
- axonal disruption in Alzheimer’s disease;
- age-related myelin degeneration;
- neuroprotective roles of glial cells during amyloid deposition;
- mechanisms of cell death and corpse removal by glial cells;
- mechanism of disruption of gliovascular interactions.
Development of methods for intravital imaging and targeted cellular manipulation: In order to obtain a comprehensive understanding of the dynamics of neurodegenerative processes, we develop and implement a variety of methodologies for high-resolution in vivo optical brain imaging and novel methods for cell-specific labeling and manipulation. Examples of techniques that we have developed include:
- spectral confocal reflectance microscopy (SCoRe) for high-resolution intravital label-free imaging of myelinated axons;
- Two photon targeted chemical-apoptotic ablation (2Phatal) of cells in vivo to understand the dynamics of glial interactions with dying cells;
- discovery of small fluorescent molecules for cell specific labeling during intravital imaging.
- Translational neuroscience: we have active efforts at developing neurotherapeutics within the field of neurodegeneration and nervous system injury. One goal is the development of treatments with cellular specificity. We have and ongoing program involving collaboration with chemists for the development of small molecules with unique properties of crossing the blood brain barrier and entering specific neural cell types to delivering therapeutic cargos. In addition, we are exploring the use of novel biologicals (antibodies and antisense oligos). We aim to apply these therapeutic agents in preclinical studies to target some of the pathological features of degeneration (axonal, myelin, microglia and vascular) that we have uncovered.