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Past Research Project Leaders

Project 2- Molecular characterization of hemoproteins targeted by S. pneumoniae to cause cell death

Jorge Vidal, PhD  Professor Department of Cell & Molecular Biology  jvidal@umc.edu

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 - Sex Differences in Addiction

Amy Kohtz, PhD Assistant Professor Department of Psychiatry & Human Behavior akohtz@umc.edu

The inability to maintain abstinence is a trademark of addiction yet effective maintenance therapies remain elusive. Women may face unique issues with substance abuse treatment, as research indicates that psychological and biological responses to drugs of abuse differ in women compared to men. Women tend to show greater drug dependence, progress more quickly from casual drug use to dependence, have greater difficulty quitting, and have shorter periods of abstinence than men. These effects have been similarly observed in female animal models. Thus, understanding circuit and molecular signatures that drive increased drug-seeking among females is critical to the development of effective SUDs therapies.  We have developed a novel behavioral model termed the seeking-persistence paradigm (SPP) that was adapted from standard drug abstinence paradigms. The seeking-persistence paradigm is used to investigate the influence of intervention during initial abstinence on long-term drug-seeking behaviors. Indeed, cocaine-seeking during initial abstinence strongly correlates with seeking after drug-abstinence. These results reflect clinical studies indicating that craving during initial abstinence predicts relapse rates. We have previously identified that the dorsal hippocampus is a crucial target for sex-specific modulation of cocaine-seeking on ED1. Prior reports show projections from the dorsal hippocampus selectively modulate memory strengthening or facilitate extinction, dependent on whether they terminate in the prelimbic cortex, or infralimbic cortex, respectively. Our preliminary data suggest that sexually-divergent projections of the dHPC to prelimbic and infralimbic cortical areas may underlie sex differences in persistent cocaine seeking during extinction.

Herein, we will test the hypothesis that hippocampal-prelimbic cortex neurocircuitry drives the behavioral expression of cocaine memory strengthening in female rats (Aim 1), and hippocampal infralimbic cortex neurocircuitry drives the behavioral expression of cocaine memory extinction in male rats (Aim 2). In each aim, we will combine chemogenetic (DREADDs), and functional genomic methods (viral tracing, RNA-sequencing, and single-cell RNA-sequencing), to ultimately provide key information on the impact of context-induced cocaine seeking behavior on relapse risk through the novel analysis of the contribution of memory systems (dHPC->PL, dHPC->IL) and sex differences therein.