The mission of the Chao Center is to identify new strategies and develop new methods for the diagnosis and treatment of Alzheimer’s disease and other neurodegenerative diseases using high-throughput biotechnologies, systems biologic modeling, drug screening and repositioning, as well as quantitative multiscale imaging. The center works closely with the Alzheimer’s and Dementia Clinical Center and the Neurodegenerative Disease Clinic of the Houston Methodist Neurological Institute translating research results to the patient bedside. It also seeks extramural grants from the National Institutes of Health and other funding agencies, as well as other philanthropy support in combating neurodegeneration and associated neurological disorders.
Drug Discovery and Repositioning for Alzheimer’s Disease
Drug-target discovery and drug repositioning in Alzheimer’s disease using bioinformatics and systems biology methods
Better understanding of the pathophysiology of Alzheimer’s disease at the early stages will help make breakthroughs for developing effective therapeutics. In this project, we apply bioinformatics and systems biology methods to examine the mechanisms and signaling pathways underlying synapse abnormalities in both cellular and mouse models of Alzheimer’s disease in order to discover potential drug targets and repurpose known drugs for new targets.
High-content screening for neural stem-cell differentiation
We are developing novel high-content screening assays and associated bioinformatics analysis and modeling software that can be used for neural stem-cell research and drug discovery. Using these assays, we carry out screening for reagents that can regulate the self-renewal and differentiation of neural stem cells.
High-content drug screening and quantification of neurite outgrowth
Large-scale compound screening has been impeded by the lack of automated tools to assess changes in neurites. Through a project funded by the National Institutes of Health, we recently developed a software package, NeuriteIQ, for the automated labeling and quantification of neuronal processes and dendritic spine morphology analysis. Armed with this powerful tool, we are carrying out a screen of all known clinical compounds. We currently have collected a library of more than 3,000 compounds.
High-content screening and analysis of dendrite spine morphology
Acquisition and quantitative analysis of high-resolution images of dendritic spines are challenging tasks but are necessary for the study of animal models of neurological and psychiatric diseases. Currently available methods for automated dendritic spine detection are, for the most part, customized for two-dimensional image slices, not volumetric three-dimensional images. Using the NeuronIQ software package, we intend to develop a fully automated method for the detection and segmentation of dendritic spines from three-dimensional confocal microscopy images; neuron types include normal neurons, degenerating neurons and medium-sized spiny neurons. Automated detection is critical for the development of new three-dimensional neuronal assays that can be used to screen drugs and study their therapeutic effects.
High-content analysis of neuronal synaptic activity
We are developing novel image-based assays to measure neuronal synapse activity. Traditional assays using electrophysiology are demanding and have very low throughput. We are developing novel image-processing programs for automated image-based synapse assays such as the FM dye assay. With automation, the assay can be carried out in a high-throughput manner, so that studies such as genome-wide screening and drug screening can be carried out.
Stem-Cell Medicine for Alzheimer’s Disease
Genetically engineered neural stem cells for neuroregeneration
We are developing genetically engineered neural stem cells for the treatment of neurodegenerative diseases. Genetic modification is used to enhance the capability of neural stem cells and also to enable us to control the activity of the cells after transplant, thus making neural stem cells safer and transplant medicine more efficient.
Optogenetics for Alzheimer’s Disease Studies
Optogenetic manipulation of cholinergic/astrocyte coupling for defective neurovascular coupling and network dysfunction
Neurovascular coupling is disrupted in patients with Alzheimer’s disease, causing cholinergic neurons to undergo massive die-off and astrocytes to proliferate greatly. Normally, cholinergic signaling activates astrocytes, increases blood flow and disrupts network synchrony; network synchrony can lead to seizures and neurodegeneration. This project uses optogenetic technology and bioinformatics methods to investigate how activation of cholinergic neurons reverses these phenotypes and how early intervention must begin.
Photoacoustic imaging of neonatal hypoxic-ischemic encephalopathy
Hypoxic-ischemic brain injury in newborns remains a major cause of long-term disability among survivors. Hypoxia-ischemia trigger sequential cascades of neurotoxic events that are initiated within hours, last for days or weeks after injury and result in prominent neuronal loss. An imaging method that can detect damaged areas early after hypoxia-ischemia would be very valuable for identifying high-risk newborns for neuroprotective treatment.
Multimodal neuroimaging and gene expression studies of autism spectrum disorders
Autism spectrum disorders are characterized by impairments in social interaction and cognitive abilities, which are typically identified before the age of three years. Studies have suggested that the deficit of physical connectivity among different regions of the brain, rather than a localized region, might be the culprit in autism spectrum disorders. A newly developed neuroimaging technique, diffusion tensor imaging, can be used to track white matter fiber pathways and reconstruct brain connectivity circuitry.