Singh Lab Research
The Singh Lab is investigating how brain vascular dysfunction initiates a cascade of effects leading to neurodegeneration and cognitive impairment in neurological disorders. The three key areas of active interest are:
- Alzheimer’s disease
- Flavivirus encephalitis
Alzheimer’s disease is prominently characterized by cerebral β-amyloidosis and cerebral amyloid angiopathy, caused by deposition of the toxic amyloid-β peptide in the brain and cerebral blood vessels. A growing body of evidence implicates amyloid-β-linked cerebral arterial dysfunction to dementia in Alzheimer’s disease. Cerebral amyloid angiopathy is almost universally found in AD patients and is a powerful and independent risk factor for ischemic stroke, cerebral hemorrhage and cognitive decline. The Singh Lab is investigating the factors influencing the influx, efflux and paravascular transport of toxic Aβ peptide in the brain. The lab is studying the cellular and molecular mechanisms in cerebral blood vessels and pathological events leading to neurovascular dysfunction, neuroinflammation and impaired neural activity. A few key molecules under investigation are NOX2, STAT3, VEGF and proinflammatory mediators.
The Singh Lab is studying ischemic stroke, subarachnoid hemorrhage and germinal matrix hemorrhage. Aneurysmal subarachnoid hemorrhage is a devastating form of hemorrhagic stroke causing a very high mortality and long-term cognitive deficits. Most of the long-term morbidity relates to serious problems with memory, emotional changes and learning disability. Similarly, in infants, germinal matrix hemorrhage, characterized by bleeding into the subependymal germinal matrix in the brain, is a major complication. The lab is looking into the molecular mechanisms that contribute to early brain injury and delayed cerebral ischemia, which is induced by delayed onset large artery vasospasm and microvascular defects. The key molecules under investigation are metalloproteases, cyclophilin A and proinflammatory mediators. The lab is also investigating synaptic dysfunction and functional reactivity in rodent models of brain hemorrhage. The goal is to identify therapeutically targetable molecules and biomarkers for subarachnoid hemorrhage and germinal matrix hemorrhage.
Flavivirus, such as dengue, Zika and Japanese encephalitis viruses, are transmitted via the bite of an infected mosquito. The virus goes into the bloodstream and sometimes crosses the blood-brain barrier and infects the brain, leading to encephalitis. An intact neurovascular unit at blood vessels, comprising vascular cells, glial cells and neurons, provides a strong barrier against the invasion of microbes into the brain. Vascular cells, such as endothelial cells and pericytes, maintain the integrity of the blood-brain barrier. The blood-brain barrier leakage of blood-derived toxic macromolecules into the brain leads to secondary neurodegenerative changes. The Singh Lab is investigating how flavivirus, such as dengue virus, compromises the neurovascular unit to enter into the brain and cause neurodegeneration.
Selected Research Tools and Techniques
- • Multi-photon microscopy
• High-speed confocal microscopy
• Cerebral blood flow measurements
• In vivo neurovascular physiology
• Blood-brain barrier transport
• Pulse chase
• Protein-ligand interaction kinetics
• Laser-capture microdissection
• Neurobehavioral analysis
Hope Center: https://hopecenter.wustl.edu/
Alzheimer’s Association: http://www.alz.org/
Brain Aneurysm Foundation: http://www.bafound.org/
Hydrocephalous Association: http://www.hydroassoc.org/
American Stroke Association: http://www.strokeassociation.org/STROKEORG/