Project 1- Molecular Mechanisms of Memory Consolidation in the Amygdala-Hippocampal Circuit
Assistant Professor, Department of Psychiatry & Human Behavior
Sleep and memory dysfunction are key features across many psychiatric disorders. Memories are strengthened during sleep , a process that may be disrupted in people with psychiatric disorders. For example, patients with schizophrenia commonly display sleep disturbances and memory consolidation deficits. In comparison, people suffering from post-traumatic stress disorder have sleep disruption and nightmares associated with heightened fear memories.
A growing number of studies support the theory that infrequently used synapses are decreased during sleep to strengthen memory processing by enhancing the signal to noise ratio of connections in the brain.
Our published and preliminary data demonstrates that brain synapses in neurons that encoded fear memory are strengthened during sleep while other synapses are largely decreased. Furthermore, our data pointing to differences between two brain regions involved in processing emotional memories, the amygdala and the hippocampus, indicates that memory processes in two key areas of the emotional memory circuit are differentially regulated during sleep.
There is a critical knowledge gap regarding the molecular pathways involved in strengthening memories during sleep. Our studies will use a combination of state-of-the-art single nucleus RNA sequencing, spatial transcriptomics and targeted mass spectrometry along with a novel transgenic mouse model, and complementary human brain postmortem studies, to create a much-needed foundation of molecular signaling pathways involved in upscaling and downscaling of synapses in the fear memory circuit during sleep and identify new molecules involved in this process.
The expected data will serve as a foundation for future studies examining disruption of these pathways in psychiatric disorders, and studies designed to identify novel targets for therapeutic strategies.
Project 2- Molecular characterization of hemoproteins targeted by S. pneumoniae to cause cell death
Associate Professor, Department of Cell & Molecular Biology
Streptococcus pneumoniae (Spn) colonizes the lungs leading to million cases of invasive pneumococcal disease (IPD) and ∼1 million deaths worldwide annually. Spn produces hydrogen peroxide (Spn-H2O2) that causes cytotoxicity and it is essential to cause IPD. The pathophysiology of IPD includes subcellular mitochondrial damage, and apoptosis in a variety of cell types. Apoptosis in cell cultures, and in an animal model of Spn pneumonia, required of H2O2 but details of the molecular mechanism have not been studied. We demonstrated that Spn-H2O2 oxidizes hemoproteins including hemoglobin and cytochrome C, the latter a key molecule triggering apoptosis, releasing heme. Since mitochondria are essential for life, and the release of cytochrome C from the mitochondria induces cell death, we hypothesize that oxidation of intracellular hemoproteins, catalyzed by Spn-H2O2, drives the pathophysiology of IPD. Molecular physiological, genetics, and biochemical approaches, leveraged by the Molecular Center of Health and Disease (MCHD), will be utilized to assess this innovative hypothesis. Dissecting the molecular mechanism will provide us with new targets for interventions to reduce the burden of pneumococcal disease.
Project 3 - Host-pathogen molecular and cardiovascular interaction during influenza infection
AssistantProfessor, Department of Cell & Molecular Biology
Influenza viral infection impacts up to 41 million people per year and can have significant impacts on morbidity and mortality. The detection of subtle changes in cardiovascular physiology in response to influenza infection is not only important for earlier diagnosis and better prognosis of symptomatic carriers, but also useful to diagnose asymptomatic carriers of the virus and provide better infectious disease surveillance.
Overall, we hypothesize that a localized inflammatory event in the respiratory system caused by the influenza virus infection leads to systemic changes in normal cardiovascular physiology, biomarkers, and viral genomic heterogeneity that can be altered by obesity and timely admission of antiviral therapeutics. The identification of novel biomarkers during an inflammatory event could significantly improve predictions for cardiovascular events. Additionally, more thorough genomic investigation of replicating influenza populations can lead to better surveillance and prediction of ongoing and emerging events.
We hope to modify cardiovascular events caused by respiratory virus infection (both during and after) with proinflammatory state of obese mice or reduction of inflammatory events in a timely manner with varying oseltamivir treatment timings. The expectation is to define markers that are present during an influenza virus infection that correlate with disease and changes in physiological homeostasis specifically for each inflammatory state (proinflammatory caused by obesity and anti-inflammatory caused by antivirals).
This study will investigate a major gap in knowledge by performing detailed analysis of cardiovascular physiology (histology, flow cytometry, and echocardiography), host molecular changes (RNA-seq and proteomics), and viral populations (real-time (quantitative) PCR [RT(q)-PCR] and RNA-seq) associated with localized respiratory viral infection with obesity and antiviral treatment or chemoprophylaxis.