CPRI COBRE Ignite Scholars

Caroline Geisler, Ph.D.
Assistant Professor, Department of Pharmaceutical Sciences
December 2024-present

Understanding central control of nutrient sensing and energy balance regulation is essential to treat dysregulated feeding and metabolic activity. Glial cells, notably astrocytes and tanycytes, have been increasingly implicated in central glucose sensing and appetite regulating mechanisms, and synthesize the anorexigenic factor octadecaneuropeptide (ODN) in response to postprandial signals. The dorsal vagal complex (DVC) of the hindbrain is sensitive to gut-derived and circulating nutrient satiety cues, initiates the counterregulatory response to hypoglycemia, and is densely populated with ODN releasing glia. We have demonstrated that hindbrain ODN signaling is in involved in central glucose sensing and coordination of peripheral metabolic activity, but the physiological mechanisms of ODN signaling and their relevance to metabolic disease require further investigation. Early work in the lab aims to: 1) understand the mechanisms underlying glucose stimulation of ODN signaling, 2) identify the neurocircuitry engaged by hindbrain ODN action which coordinates peripheral metabolic activity, and 3) demonstrate the targetability of ODN signaling to improve diet-induced dysfunctions of central glucose sensing and restore peripheral responsiveness to changes in fuel status that promote whole-body energy homeostasis.

Publications

Kristen McLaurin, Ph.D.
Assistant Professor, Department of Pharmaceutical Sciences
February 2024-present

Independently, opioid use disorder and chronic HIV-1 viral protein exposure induce prominent neurocognitive impairments and a profound hypodopaminergic state. To date, however, how the dopamine system responds to HIV-1 infection in the context of pre-existing alterations (i.e., as would be observed in an individual with opioid use disorder) remains unclear; a critical knowledge gap given that the opioid epidemic is fueling a surge in HIV-1. The recent extension of the chimeric HIV (EcoHIV) model of HIV-1 infection to rats has provided an opportunity to address these fundamental challenges. Accordingly, early work in the laboratory aims to: 1) Establish the threshold dose of comorbid oxycodone and HIV-1 for neurocognitive impairments; and 2) Identify how comorbid oxycodone and HIV-1 alter the function and structure of the frontal-subcortical circuit. Establishing the unique causal neural mechanisms underlying neurocognitive impairments resulting from comorbid opioid use disorder and HIV-1 are fundamental to identifying therapeutic targets for this high-risk group.

Publications

Kevin Tidgewell, Ph.D. 
 Assistant Professor, Department of Pharmaceutical Sciences
July 2023 - present

There is a pressing need to develop novel therapeutic agents against new targets for chronic pain. This project will use cyanobacterial-derived natural products as the starting point for chronic neuropathic pain drug development by targeting the sigma 2/transmembrane protein 97 (σ-2/TMEM97) receptor and other targets involved in pain. The σ-2/TMEM97 receptor has been pharmacologically known for over 40 years but only since 2017 has the molecular identity and its possible role in pain been described. With a new crystal structure σ-2/TMEM97 and five studies describing the potential of σ-2/TMEM97 modulators to treat pain in rodents, this will be an area of rapid exploration and development in the coming years. Our preliminary data show selectivity of proof-of-concept cyanobacterial natural products for σ-2/TMEM97 as well as data showing analgesic effects in mice with potential to modulate human “nociceptors” in vitro with mechanisms of action identified in primary mouse dorsal root ganglion neurons. Loss of σ-2/TMEM97 leads to enhanced recovery from inflammatory pain suggesting a normally pro-nociceptive role of σ-2/TMEM97. Using cyanobacterial natural products and synthetic analogs, this project will yield i) explore their binding to and modulation of the σ-2/TMEM97 receptor and ii) improve understanding of the pharmacological and biological role of σ-2/TMEM97 in human nociceptors.

Mentors: Jurgen Rohr, Pavel Ortinski

Publications

Anel Jaramillo, Ph.D. 
Assistant Professor, Department of Pharmaceutical Sciences
February 2023 - present

Heightened anxiety and dysregulated behavioral responses to stress are key features of neuropsychiatric mood disorders (e.g., PTSD). To inform the development of effective treatments our lab investigates the mechanisms underlying heighted anxiety by combining sophisticated measures of neurocircuit activity with classic behavioral assays in rodent models. This project will investigate inhibition of stress-related neuropeptides as a target for alleviating dysregulated anxiety-like behavior and circuit activity in the extended amygdala, a core component of anxiety circuitry.

Mentors: Jill Turner, Ilhem Messaoudi Powers

Publications

Lindsay Czuba, Ph.D.
Assistant Professor, Department of Pharmaceutical Sciences
September 2022 - February 2024

Progressive human obesity is associated with systemic dysregulation of cholesterol, oxysterol, and bile acid homeostasis and is a leading cause of NAFLD, diabetes, and cardiovascular disease. Bile acids and their metabolites serve as ligands for nuclear receptors such as the farnesoid X receptor (FXR) and liver X receptor (LXR) to transcriptionally regulate lipid and cholesterol homeostasis. Gut commensal bacteria contribute significantly to the metabolism of bile acids to produce secondary bile acid metabolites. However, little is known about the individual contributions of bile acids and their secondary metabolites to gut-liver signaling and metabolic effects. Early work in the lab aims A) to identify the affinity and activity of secondary bile acid metabolites towards FXR and the bile acid transporter, ASBT and B) to develop LC-MS/MS methods to quantify bile acid metabolites and oxysterols in gut and liver tissue. Findings from these projects will provide foundational knowledge on the role of bile acid metabolites in mediating bile acid, cholesterol, and lipid homeostasis and inform future translational research on human obesity pathogenesis and its metabolic comorbidities.

Mentors: Barbara Nikolajczyk, Bjoern Bauer

Publications