Investigators
Research Project Leaders
Project 1 - Molecular Mechanisms of Memory Consolidation in the Amygdala-Hippocampal Circuit
| Assistant Professor |
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 demonstrate that brain synapses in neurons that encode 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 the disruption of these pathways in psychiatric disorders and studies designed to identify novel targets for therapeutic strategies.
Project 2 - Host-pathogen molecular and cardiovascular interaction during influenza infection
| Assistant Professor |
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 the proinflammatory state of obese mice or the 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 a 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.
Project 3 - Myeloid Intracellular Clearance as a Targetable Mechanism of Viral Persistence
 | Ramona Moles, PhD |
Monocytes are mononuclear phagocytes, which historically have been considered crucial in suppressing tumor growth by recognizing and killing tumor cells. However, the immune system does not eliminate transformed cells in cancer patients. Emerging evidence shows that in vivo monocytes exhibit an immunosuppressive phenotype that promotes cancer development rather than disease progression. Transcriptomic analyses of circulating monocytes isolated from different cancer types revealed alteration in gene expression. However, most pathways identified are not involved in the immunosuppressive phenotype, demonstrating that further studies are needed to fully understand the functional role of monocytes in cancer.
Dr. Moles' project will aim to investigate the role of monocytes in the neoplastic disease induced by the oncogenic virus HTLV-1. Adult T cell leukemia (ATL) is an incurable condition induced by the retrovirus HTLV-1. The main cellular targets of the virus are CD4+. Evidence suggests that the innate response, specifically monocytes, might be involved in HTLV-1 pathogenesis. Monocytes isolated from HTLV-1 infected individuals and ATL patients display functional alterations in their ability to differentiate and release cytokines. Our data demonstrates that HTLV-1-infected cells are resistant to monocyte-mediated engulfment. This evidence shows that the virus targets and manipulates the monocytes' functions; however, its role in HTLV-1 pathogenesis is poorly understood and represents a scientific gap in the field. Our hypothesis is that the oncovirus HTLV-1 reprograms monocytes to favor the progression of infected cells towards leukemia and support immune evasion of transformed cells.
The engulfment mediated by monocytes is a process that can be divided into three steps: phagocyte recognition of the "eat me/don't eat me" signals on the surface of target cells, and the engulfment and degradation of cargo. This proposal aims to study (Aim 1) how HTLV-1-infected cells impair the "don't eat me" signal to escape monocyte recognition, (Aim 2) studying the fate of monocytes following phagocytosis and (Aim 3) characterize the functional phenotype of monocytes in ATL patients.