Center Events

Robert J. Binder, PhD - Professor, Department of Immunology, University of Pittsburgh

During cancer immunosurveillance, dendritic cells (DCs) play a central role in orchestrating T cell responses against emerging tumors. Capture of miniscule amounts of antigen along with tumor-derived costimulatory signals can drive maturation and activation of DCs. We have shown that expression of the heat shock protein receptor CD91 on DCs is essential in the cross-priming of T cell responses in the context of nascent tumors. In this presentation, the mechanisms of the HSP-CD91 pathway will be laid out in mouse and human disease, as well as novel approaches to cancer immunotherapy borne out of our findings.

 Oct 07, 2024 @ 12:00 p.m.
 Medical Center | Upper Auditorium (3-7619)

Kumari “Kavita” Thakur, PhD - Associate Research Scientist, Division of Molecular, Cellular and Development Biology, Yale University

Abstract: Bacteria are equipped with intricate mechanisms to adapt to environmental stresses, many of which involve non-coding RNAs such as small RNAs (sRNAs) and riboswitches. These regulatory RNAs play pivotal roles in bacterial virulence, biofilm formation, and antibiotic resistance. My research focuses on unraveling the post-transcriptional regulation of gene expression in bacteria, especially through noncoding RNA-based mechanisms. I will discuss my recent work on the role of sRNAs and RNA-binding proteins, such as Hfq, in regulating bacterial responses to stress. I will highlight my discoveries on the role of intrinsically disordered domains in Hfq, a previously debated topic in the literature, which are crucial for RNA interactions and gene regulation. Additionally, I will present the discovery of a novel riboswitch that detects 8-oxoG, a product of bacterial DNA damage caused by oxidative stress, leading to gene regulation. These findings were investigated using a variety of in vivo and in vitro techniques, including genetic reporter fusions assays, RNA sequencing (RNA-seq), northern blotting, and in-line probing assays. Join us to explore the critical role of non-coding RNAs (sRNAs and riboswitches) in the regulation of gene expression and their impact in the coding world of bacteria.

Zoom: https://urmc.zoom.us/j/99319220852?pwd=IIXdtQikGkNO905Rm1flLoXnjZISK4.1

Passcode: 717782

 Oct 10, 2024 @ 10:00 a.m.
 Medical Center | K307 (3-6408)

Maggie Lesch - PhD Candidate, Immunology, Microbiology, and Virology Ph.D. Program

Colorectal cancer (CRC) is a devastating malignancy that ranks as the second leading cause of cancer-related deaths, and fourth in cancer diagnoses annually in the United States. Among CRC cases, rectal cancer (RC) comprises one-third of cases, with over 50,000 people in the US diagnosed each year. Surgical resection is a treatment option for RC, however it can greatly reduce patients’ quality of life and unfortunately, some patients still experience recurrence. Recently, treatment paradigms have shifted towards organ preservation in RC through the adoption of the watch-and-wait approach in which patients undergo total neoadjuvant treatment with active surveillance, often avoiding surgery. While approximately 30% of patients experience a complete clinical response with this approach, most have an incomplete response to neoadjuvant therapy and ultimately require surgery or further therapy. Why this binary divide occurs is poorly understood, and there are no biomarkers for predicting response. To study this question, our lab has developed a clinically relevant orthotopic murine model of RC, in which administration of Short Course Radiation Therapy (SCRT) results in recapitulation of this binary responder/nonresponder phenotype seen in patients. Our model enables the study of both phenotypes during and following treatment. Using this model, we performed a series of experiments to investigate the molecular mechanisms driving this responder/nonresponder dichotomy. Specifically, RNA-sequencing of intratumoral cell populations, following SCRT, revealed an upregulation of the Type I Interferon (IFN) signaling pathway in responder tumors when compared to nonresponders. Type I IFNs have emerged as essential cytokines that mediate the antitumor immune response. Preliminary data has confirmed that responder tumors had higher concentrations of intratumoral Type I IFN protein that were maintained throughout treatment. Blockade of the Type I IFN receptors completely abrogated the responder phenotype further emphasizing the importance of these factors in dictating the responder/nonresponder divide. To explore what may mediate this effect, we investigated the influence of the microbiome, as pathogen associated molecular patterns (PAMPs) from radio-sensitive bacteria are known to contribute to Type I IFN production. To test this, we depleted the microbiota by administering antibiotics throughout SCRT treatment. This resulted in a decrease in responder tumors, indicating that the microbiome plays a significant role in mediating the therapeutic effect. Future experiments using fecal transplants and 16s sequencing will explore whether specific bacteria or subsets of bacteria govern the treatment response. These studies are clinically translatable and may identify noninvasive predictive biomarkers, with the potential to improve the efficacy of SCRT and increase the number of patients who respond to treatment.

 Oct 10, 2024 @ 12:00 p.m.
 Medical Center | K307 (3-6408)

Nicholas Pokorzynski, PhD - Postdoctoral Research Associate, Department of Microbial Pathogenesis, Yale University School of Medicine

Abstract: Glucose is the preferred carbon source of most microorganisms. Why, then, does glucose lose its preferred status when the intracellular pathogen Salmonella enterica serovar Typhimurium is inside mammalian macrophages? We now establish that this surprising behavior results from macrophages provoking cytoplasmic Mg2+ starvation in S. Typhimurirum. Cytoplasmic Mg2+ starvation drastically reduces synthesis of cyclic adenosine monophosphate (cAMP), the allosteric activator of the cAMP receptor protein (CRP), master regulator of carbon utilization. The resulting reduction in cAMP concentration decreases transcription of CRP-cAMP-activated carbon utilization determinants, which reduces uptake of corresponding carbon sources and modifies metabolism. Rendering CRP activity cAMP independent or supplementation with exogenous cAMP overcomes transcriptional, transport, and metabolic restrictions caused by cytoplasmic Mg2+ starvation. S. Typhimurium’s reduced glucose preference inside macrophages reflects that transcription of the glucose uptake gene is far more sensitive to the amount of active CRP protein than transcription of other carbon uptake genes. By reducing CRP-cAMP activity, the intramacrophage environment restricts S. Typhimurium metabolism, consistent with decreased protein synthesis that slows pathogen growth, heightening tolerance to antimicrobial agents.

Zoom: https://urmc.zoom.us/j/94337654366?pwd=pezThiio47PqoHmC4aTy5bflDnEovb.1

Passcode: 051922

 Oct 14, 2024 @ 12:00 p.m.
 Medical Center | K307 (3-6408)