Discovery Sciences Emerging Scholars Lectures
This lecture series features young scientists making notable discoveries as postdoctoral fellows or early career faculty.
Friday, April 2, 12:00 pm via Zoom, Chrystal Starbird, Ph.D., Postdoctoral Fellow, Yale University, Department of Pharmacology: “Structural Basis of TAM Receptor Oligomerization.” Co-sponsored by the Department of Biochemistry. Receptor tyrosine kinases are key regulators of a wide range of biological functions and share a single transmembrane helix that links an extracellular domain to an intracellular kinase domain. How a single helix promotes the large diversity of signaling mediated by RTKs has long been a question of interest. Classically, RTKs are considered to be activated by ligand-induced dimerization. However, my work on the TAM subfamily of receptors has shown unique requirements for oligomerization and suggests that our current simple view of receptor activation is insufficient to explain the observed complexity of receptor signaling. Starbird CV Starbird Flyer Get Zoom info here.
Friday, December 11, 12:00 pm via Zoom, Chelsey Spriggs, Ph.D., Postdoctoral Fellow, University of Michigan Medical Center: “Viral hijacking of host molecular motors to promote nuclear entry.” Co-sponsored by the Department of Biochemistry. During entry, most DNA viruses must navigate the crowded cellular environment to reach the nucleus where transcription and replication of the viral genome occur. How polyomavirus (PyV), a small DNA tumor virus, accomplishes this feat is not well-understood. We reported that cytoplasmic dynein motor activity is required to disassemble PyV once in the cytosol and to target the disassembled virus to the nucleus. However, the precise mechanism underlying these dynein-dependent steps remain unclear. Investigating the role of dynein cargo adaptor proteins in this process, we have discovered an unexpected and novel function of the bicaudal-D adaptors in virus infection. Spriggs CV Spriggs Flyer Get Zoom info here.
Tuesday, December 8, 4:00 pm via Zoom, Christina Termini, Ph.D., University of California President’s Postdoctoral Fellow, UCLA: “Leveraging proteoglycans for hematopoietic stem cell regeneration.” Co-sponsored by the Department of Cell and Developmental Biology. Although hematopoietic stem cells (HSCs) comprise less than 0.01% of the adult bone marrow, this rare cell population is capable of supporting the hematopoietic needs of an organism throughout their lifetime. However, when HSCs are unable to adapt to hematopoietic stress, life-threatening complications can arise. As such, it is essential we elucidate the basic regulatory mechanisms that underscore HSC regeneration. My postdoctoral research identified a novel surface marker that both identifies and regulates HSCs through parallel mechanisms. This surface marker is from the heparan sulfate family of proteoglycans and can be used to enrich for long-term HSCs capable of enhanced hematopoietic engraftment, expansion and self-renewal ability. Loss of function analyses determined that this heparan sulfate proteoglycan regulates HSC maintenance and myelopoiesis through alterations in cell cycling. Additional work analyzing how proteoglycans can be utilized to accelerate hematopoietic recovery after myelosuppression will be presented. Termini CV Termini Flyer Get Zoom info here.
Thursday, November 19, 9:30 am via Zoom, Cornelius Taabazuing, Ph.D., Postdoctoral Fellow, Memorial Sloan-Kettering Cancer Center: “Investigating the molecular regulation and function of death signaling complexes.” Co-sponsored by the Department of Molecular Physiology & Biophysics. The cellular response to danger signals such as pathogens or DNA damage is important for survival and many diseases. The response is usually mediated by large multiprotein death signaling complexes that can either eliminate the damaged cells or promote homeostatic restoration pathways. However, the specific inputs that initiate the death signaling complex formation as well as the downstream signaling pathways activated by these complexes are not well understood. Here, we demonstrate how small molecule inhibitors of the serine peptidases, DPP8/9, induce formation of the CARD8 and NLRP1 inflammasomes, which activate caspase-1 to cause an immunostimulatory type of death called pyroptosis. Taabazuing CV Taabazuing Flyer Get Zoom info here.
Thursday, October 29, 9:30 am via Zoom, Melanie McReynolds, Ph.D., HHMI Hanna H. Gray Fellow, Princeton University, “NAD+ flux is maintained in aged mice.” Co-sponsored by the Department of Molecular Physiology & Biophysics. NAD+ is an essential coenzyme found in all living cells. NAD+ concentrations decline during aging, but whether this reflects impaired production or accelerated consumption remains unclear. Here we employed isotope tracing and mass spectrometry to probe NAD+ metabolism across tissues in aged mice. In 25-month-old mice, we observe modest tissue NAD+ depletion without significant changes in circulating NAD+ precursors. Isotope tracing showed unimpaired synthesis of circulating nicotinamide from tryptophan, and maintained flux of circulating nicotinamide into tissue NAD+ pools. Although absolute NAD+ biosynthetic flux was maintained in most tissues of aged mice, fractional tissue NAD+ labeling from infused labeled nicotinamide was modestly accelerated. Long-term calorie restriction partially mitigated age-associated NAD+ decline despite decreasing NAD+ synthesis. Thus, age-related decline in NAD+ is driven by increased NAD+ consumer activity rather than impaired production. McReynolds CV McReynolds Flyer
Thursday, April 9, Sonya Neal, Assistant Professor, UC-San Diego, 4:00 pm, 1220 MRB III: “The role of rhomboid pseudoproteases in ERADicating misfolded membrane substrates.” My newly-established lab strives to understand the basic biology of endoplasmic reticulum-associated protein degradation (ERAD), a critical pathway which removes misfolded proteins both from the ER membrane and lumen. Exporting misfolded substrates from the ER for later cytosolic degradation is a universal feature of eukaryotic cells. Despite intense efforts, the mechanism of ER export for integral membrane substrates has remained contentious and unclear. Using a self-ubiquitinating substrate (SUS) and the new microarray library to query all yeast genes, I discovered a central factor in protein export, the rhomboid protein Dfm1. Indeed, Dfm1 is required for removing multiple types of misfolded integral membrane substrates. Accordingly, we are interested in studying the mammalian retrotranslocation pathway in both a cellular and organismal context. Knowledge of the proteins involved in the universal and critical process of retrotranslocation will open avenues for therapeutic approaches to attack diseases upregulated in retrotranslocation (cancers), or to ameliorate diseases where proteins are prematurely retrotranslocated (cystic fibrosis). Neal CV Neal Flyer
Antentor “A.J.” Hinton, Jr.
Thursday, March 5, Antentor “A.J.” Hinton, Jr., Ph.D., 9:30 am, 206 Preston Research Building: “OPA-1 Deficiency in Skeletal Muscle Increases Mitochondria ER Contact Formation Through an ATF-4 Dependent Mechanism.” Dr. Hinton, Jr. is a Postdoctoral Research Fellow in the Department of Internal Medicine, University of Iowa. In the laboratory of E. Dale Abel we have found that reduction in OPA1 (Optic Atrophy 1, a mitochondrial dynamin-like GTPase) expression in skeletal muscle results in endoplasmic reticulum (ER) stress response and FGF21 secretion. We predicted that there was an association between the loss of OPA1, an increase in ER-Mitochondrial Contact sites, and prevalence of diabetes. Mitochondrial endoplasmic reticulum contact sites (MERCs) are specialized membranes that are enriched with specific proteins believed to be important for calcium flux, lipid transfer, and mitochondria morphology. This observation provides a plausible mechanism linking altered mitochondrial dynamics with the activation of the ER stress response pathway and may give novel insight into how some patients develop insulin resistance. We propose to use this information to provide the foundation for future research that will lead to the discovery of more effective biomarkers that identify insulin resistance in skeletal muscle. Hinton CV Hinton Flyer
Tuesday, December 3, Chantell Evans, 4:00 pm, 206 Preston Research Building: “The Role of Optineurin in Neuronal Mitophagy.” Dr. Evans is an HHMI Hannah H. Gray Postdoctoral Fellow at the University of Pennsylvania. Mitophagy, the selective removal of damaged mitochondria, is thought to be critical to maintain neuronal homeostasis. Mutations in proteins implicated in mitophagy, including PINK1, Parkin, OPTN, and TBK1, cause Parkinson’s disease or ALS, suggesting defective mitochondrial turnover contributes to neurodegeneration. To test this hypothesis, we used mild oxidative stress to induce low levels of mitochondrial damage in hippocampal neurons. We observed the sequential recruitment of Parkin, TBK1, and OPTN to depolarized mitochondria followed by their sequestration into autophagosomes, and determined this pathway was compartmentally restricted to the soma. Further, acidification of mitophagosomes was remarkably slow in neurons and overall was a rate-limiting step in the mitophagy pathway. Expression of an ALS-linked OPTN mutation disrupted the integrity of the mitochondrial network and this effect was exacerbated by oxidative stress. We propose that the slow kinetics of mitophagy enhance neuronal susceptibility to disease-associated mutations in the pathway, leading to neurodegeneration. Evans CV Evans Flyer
Tuesday, November 12, Reginald D. Cannady, 4:00 pm, 512 Light Hall: “Probing Novel Targets to Reduce Heavy Drinking in Models of Alcohol Use Disorder.” Dr. Cannady is a Postdoctoral Research Fellow at the Medical University of South Carolina. Individuals with alcohol use disorder (AUD) show an inability to regulate alcohol consumption and seeking behavior. Although, there are FDA‐approved medications for AUD, they have limited efficacy. My work examines neuroadaptations caused by chronic alcohol experience and focuses on identifying neuronal targets to reduce heavy drinking using several rodent models of alcohol addiction. This presentation will discuss the validation of KV3 potassium channels as a potential therapeutic target to reduce alcohol consumption in preclinical models of alcohol dependence. Cannady CV Cannady Flyer
Tuesday, October 22, Sabena Conley, 4:00 pm, 512 Light Hall: “Obesity-Induced Mesenchymal Stem Cell Senescence and Dysfunction.” Dr. Conley is a Research Fellow at the Mayo Clinic College of Medicine, Rochester, Minnesota. Endogenous mesenchymal stem cells (MSC) mediate tissue repair, but obesity might potentially impair their regenerative potency. The adipose tissue microenvironment in obesity stimulates cellular senescence (CS), an irreversible cell cycle arrest that prompts an inflammatory, senescent-associated secretory phenotype (SASP). To test the hypothesis that obesity induces CS and dysfunction in MSC from obese patients, we harvested and evaluated MSC from fat tissue collected from obese and non-obese patients undergoing surgery at Mayo Clinic. Obese-MSC demonstrated increased CS and SASP and lower proliferation than non-obese-MSC. Therefore, human obesity induces senescence in adipose tissue-derived MSC, which might interfere with their repair capacity. Conley CV Conley Flyer
Thursday, April 25, Timothy Downing, 4:00 pm, 512 Light Hall: “Synthetic Genome Regulation for Cell and Tissue Engineering.“ Dr. Downing is an Assistant Professor in the Department of Biomedical Engineering, University of California, Irvine. The Downing Lab is interested in understanding how the chemical and biophysical microenvironment influences adult cell behavior and phenotype through epigenetic gene regulatory mechanisms. We hope to use this information in the design of next-generation biomaterials. This presentation will describe how specific cues (e.g., topography and matrix stiffness) within cellular microenvironments can influence epigenetic state and facilitate the reprogramming of somatic cells back to pluripotency. Web Downing Flyer
Tuesday, March 5, Luis Natividad, 4:00 pm, 206 Preston Research Building: “Impaired Endocannabinoid Signaling in Stress and Addiction“. Co-sponsored by the Vanderbilt Center for Addiction Research. Dr. Natividad is a Senior Research Associate, The Scripps Research Institute, La Jolla. Abstract: “Heavy alcohol consumption induces long-term problems with stress and anxiety, and is common among dependent individuals who are co-diagnosed with mood disorders. As endocanna-binoids (e.g., N-arachidonoylethanolamine and 2-arachidonoylglycerol) provide an important mechanism of inhibitory constraint in the regulation of stress circuits, Dr. Natividad will elaborate more on the premise of dysregulated endocannabinoid signaling influenced by chronic alcohol exposure relative to observations in a genetic model of “innate alcohol dependence” within the central nucleus of the amygdala.” Natividad CV Web Natividad Flyer
Thursday, February 7, Stacey Finley, 4:00 pm, 512 Light Hall: “Systems Biology Approaches to Predict the Dynamics of Biochemical Networks in Cancer.” Dr. Finley is an Assistant Professor at the University of Southern California. Abstract: “Systems biology approaches, including computational models, provide a framework to optimize effective therapeutic strategies for cancer. My research group develops mechanistic models of biochemical networks in cancer to study cancer immunotherapy, tumor angiogenesis, and cancer metabolism. Our models provide insight into the dynamics of the biochemical pathways in cancer and enable the development of novel therapeutics.” Finley CV Website Finley Flyer
Thursday, December 6, Angelina Hernandez-Carretero, 9:30 am, 206 Preston Research Building: “Novel Regulators of Obesity-Induced Insulin Resistance and Diabetes.” Dr. Hernandez-Carretero is a Staff Scientist at the City of Hope Beckman Research Institute. “Further investigation is needed to understand the molecular players involved in obesity-induced insulin resistance. We have utilized a dietary switch mouse model to perform transcriptomics of the skeletal muscle, and compared these findings with RNA-seq of human obese- diabetic muscle. This multispecies approach identified key genes that tracked with the insulin resistant state in both mouse and human muscle, including Cysteine and glycine-rich protein 3 (Csrp3). Csrp3 expression is decreased in obese-insulin resistant muscle and plays an important role in insulin-stimulated glucose uptake.” Flyer Hernandez-Carretero CV
Tuesday, November 13, Luisa Escobar-Hoyos, 4:00 pm, 206 Preston Research Building: “Targeting RAS and mutant p53: Discovery of RNA splicing as a therapeutic vulnerability in pancreatic cancer.” Dr. Escobar-Hoyos is a Postdoctoral Research Fellow at Memorial Sloan Kettering Cancer Center and Research Assistant Professor at Stony Brook University. “We recently discovered a novel mechanism of cooperation between the two most common oncogenes in pancreatic cancer, oncogenic RAS and neomorphic mutant p53, uncovering a potential therapeutic opportunity to target tumors that bear these mutations. Specifically, we found that mutant p53 causes aberrant splicing of GAP proteins, the negative regulators of RAS, resulting in expression of inactive GAP proteins (polyC GAPs), and ultimately promoting oncogenic RAS signaling. In addition, we identified that pancreatic tumors in mouse models depend on expression of polyC GAPs and splicing machinery proteins, as genetic and chemical inhibition of these proteins caused decrease in tumor growth, number of metastases and tripled the survival time of animals. These studies identified these proteins as new targets for tumors with neomorphic p53 and oncogenic KRAS. We expect to identify novel and specific dependencies of PDAC cells by studying and targeting specific alternatively spliced products and/or manipulating the function of splicing factors in the background of multiple forms of mutated TP53, to provide the foundation for future research that will lead to the development of more effective approaches to treat PDAC patients, improving their survival and quality of life.” Flyer Escobar-Hoyos CV
Wednesday, October 10, Leonard Alfredo Harris, Vanderbilt University, 4:00 pm, 512 Light Hall: “Bet Hedging as a Survival Strategy in Complex Biological Systems and Cancer.” Cells are complex, dynamic systems capable of initiating internal biochemical programs and adjusting their behavior in response to microenvironmental signals and stressors. Under the general term “phenotypic plasticity,” this phenomenon underlies important biological processes such as stem cell differentiation and epithelial-to-mesenchymal transitions. In bacteria, isogenic cell populations are known to exploit plasticity by phenotypically diversifying to increase their chances of survival to catastrophic external challenges, a strategy known as “bet hedging.” Recent evidence suggests that cancer cells may employ a similar strategy to survive the initial onslaught of anticancer therapeutics. Understanding the complex biochemical networks that underlie signal propagation and cell fate decisions is thus critical for improving treatments of various human diseases, including cancer. Here, I describe the biochemical basis for phenotypic plasticity within the framework of “Waddington landscapes,” present evidence for its role in anticancer drug resistance in non-small cell lung cancer and melanoma populations treated with targeted drugs, and discuss initial work toward constructing a detailed computational model of the biochemical machinery underlying cellular responses to external perturbations. Flyer CV
Thursday, May 3: Ishmail Abdus-Saboor, University of Pennsylvania, 4:00 pm, 512 Light Hall: “Genetic Interrogation of Neural Circuit Mechanisms for Pain.” The nervous system is exquisitely tuned to mount the appropriate behavioral response to somatosensory stimuli ranging from a gentle caress to a harsh mechanical insult. How our nervous systems encode this information, from the level of sensory neuron activation in the skin up towards the central nervous system, in both normal and diseased states, remains enigmatic. We are working to uncover the mechanisms governing sensory encoding of touch, itch, and pain. Using optogenetics, quantitative analysis of animal behavior, and in vivo calcium imaging we have 1) determined how a population of pain-sensing neurons have unique morphological and physiological outputs depending upon body location, and 2) developed a new behavioral platform using high-speed videography, statistics, and machine learning to distinguish between innocuous versus painful behavior responses. Flyer CV Abdus-Saboor Lab
Thursday, March 1: Gustavo Silva, Duke University, 4:00 pm, 406 Preston Research Building: “K63 ubiquitin and the regulation of translation in response to oxidative stress.” Ubiquitin is a prominent post-translational modification, which signals extensively beyond protein degradation. In this talk, Dr. Silva will present his research on how ubiquitin modifies ribosomes and controls cell resistance to stress. Flyer CV
Thursday, February 1: Dionna Williams, Johns Hopkins University, 4:00 pm, 512 Light Hall: “Beyond GPCR Recycling: B-Arrestin as a Neuroprotective Modulator of Innate Immune Responses.” Dr. Williams’ talk will focus on the organ-specific, immunomodulatory roles of B-arrestin that serve to suppress chronic immune activation during viral infection of the brain. Flyer CV
Thursday, December 14: Arion Kennedy, Vanderbilt University, 4:00 pm, 206 Preston Research Building: “CD8+ T Cells Regulate Liver Injury In Obesity-Related Nonalcoholic Fatty Liver Disease.” The incidence of NAFLD has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in obesity-associated NAFLD. Dr. Kennedy’s talk will focus on the role of CD8+ T cells in the development of obesity- associated NAFLD. Flyer CV
Thursday, November 16: Avery Posey, Jr., University of Pennsylvania, 12:00 pm, 898 Preston Research Building: “Accelerating CAR T Cells from the Model T to Driverless.” Dr. Posey will discuss engineered T cell therapies developed to treat cancer, including progress and imitations of translating the success of leukemia treatments to solid tumor treatments. Flyer CV
October 5: Sade Spencer, Medical University of South Carolina, 4:00 pm, 206 Preston Research Building: “Dopaminergic Regulation of Relapse-Dependent Glutamatergic Plasticity.” Dr. Spencer will present her modified cue-cocaine relapse model and the alterations in transient synaptic plasticity associated with relapse observed in the nucleus accumbens. She will also present newer data pertaining to the relationship between dopamine and glutamate during relapse, and how this impacts synaptic function. Flyer CV
April 13: Stephanie Correa, UCLA, 4:00 pm, 206 Preston Research Building: “Sex-Specific Neural Regulation of Energy Balance.” The focus of Dr. Correa’s lab is understanding how reproductive hormones affect metabolic health and disease. Flyer Photos
March 16: Rene Raphemot, Duke University, 4:00 pm, 206 Preston Research Building: “A Genomic Screen Reveals New Host Factors Critical to Liver-Stage Malaria.” Dr. Raphemot studies host-parasite interactions during the liver-stage of malaria infection. His goal is to understand host-related factors that are exploited by the parasite. Flyer Reporter Article Photos