Project 1
Stroke & brain injury. How do neurons protect themselves when faced with acute damage? Acute injury to neurons occurs during stroke, traumatic brain injuries, and seizures. Much of the damage to neurons under these conditions is driven by excess release of the excitatory neurotransmitter glutamate. This type of acute injury is known as “excitotoxicity.” Excitotoxicity also contributes to neurodegenerative diseases such as Alzheimer’s. Like most cells in the body, neurons mount protective responses in an attempt to counteract dangerous conditions like hypoxia or excitotoxicity. We are characterizing the pro-survival responses of neurons, especially how cytoskeletal reorganization orchestrates such neuroprotection. Our goal is to identify potential new therapeutic approaches to encourage neurons to “defend themselves” in times of injury, thereby reducing the long-term consequences of brain and spinal cord damage.
Project 2
Autism. How do disruptions in the wiring of neural connections contribute to autism? Autism spectrum disorders are complex, multi-factor neurodevelopmental conditions that affect social and emotional communication. Symptoms can range from very mild to very severe, and can be present in individuals with typical, extremely high, or extremely impaired intellectual function. The underlying causes of autism remain poorly understood, but research in recent years indicates that both genetic factors and environmental factors can contribute to the disorder. Evidence suggests that autism begins with altered circuit wiring during early fetal or embryonic development. (This is one of the many reasons why scientists are confident that childhood vaccines do not cause autism). Our lab is partnering with other UCSD and Salk Institute researchers to apply CRISPR-based methods to generate autism-related mutations in human induced pluripotent stem cells (iPSCs). Using these powerful tools, we have developed microscopy-based phenotype screens to assay neurite outgrowth and synapse formation, as well as responses to cellular stress. We apply high content screening (HCS) technology to quantify the structural and metabolic features of human neurons across autism disease models.
Project 3
Energy homeostasis. Scientists have known for decades that the brain uses at least 20% of the body’s energy while occupying only 2% of body weight. This high metabolic demand stems from many neural processes that support network signaling, the main function of the nervous system. We are investigating how neurons efficiently manage their limited energy budget while still supporting robust signaling and neural plasticity – demands which change over an organism’s sleep-wake cycle. Our lab is applying its expertise in subcellular imaging to investigate how neurons regulate their main sources of cellular ATP, and which subcellular functions account for most energy consumption. We are especially interested in how these metabolic features change in association with neuronal network activity patterns that resemble the sleep-wake cycle. We are collaborating with colleagues who apply computational modeling to better understand these interconnected systems, and to predict how perturbations affect synapse structure and plasticity.