COBRE CMADP 10th Anniversary Symposium Schedule
Tuesday, May 23, 2023
School of Pharmacy, Room 1020
8:30am - 12:15pm
8:30 - 8:45am: Opening remarks by Susan Lunte, PI and Director of COBRE CMADP
8:45 - 9:35am: Keynote speaker Carol Saunders, Clinical Director of Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City
"A Decade of Genomic Medicine at Children’s Mercy: What We’ve Learned and Where We are Headed"
The last decade has seen an explosion of new technology, resulting in faster and cheaper sequencing. This has brought an explosion of data, enabling new diagnoses and novel gene-disease associations. The result has been a paradigm switch in the clinic—from sequencing individual genes based on key phenotypic features to reverse phenotyping based on genomic testing. Despite our successes, there continue to be difficulties in variant interpretation and technical hurdles in the detection of certain types of variants. I will discuss this journey, including our work in characterizing phenotypic expansion, new gene discovery, and new method validation to improve our diagnostic rate.
9:35 - 9:45am: Break
9:45 - 10:10am: Michael Veeman, Associate Professor of Biology, KSU
"Asymmetric cell division in the Ciona posterior neuromesodermal b6.5 lineage"
In the model tunicate Ciona, secondary muscle cells at the tip of the developing tail are closely related by lineage to the posterior neural tube. Potential homology between posterior neuromesodermal progenitors in vertebrates and tunicates is difficult to assess, however, because the Ciona posterior neuromesodermal lineages derived from the b6.5 blastomere are poorly understood and represent the greatest gap in understanding the main cell fate decisions in the intensively studied Ciona embryo. We recently used scRNAseq to identify markers for 3 distinct cell types in the b6.5 lineage at the mid-gastrula stage: b8.18/20 dorsal midline tail epidermal precursors, b8.19 posterior dorsal neural tube precursors and b8.17 tailtip neural/muscle precursors. The genes differentially expressed between these three cell types include several mitochondrial transcripts. We have pursued this using Mitotracker staining and find there are major differences in both the intensity and the texture of staining between b8.18/20, b8.17 and b8.19. We also find that b8.17 undergoes a deeply unequal cleavage such that its posterior daughter b9.34 (tail tip muscle) is far larger than in its anterior daughter b9.33 (tail tip neural). We are currently dissecting the mechanisms controlling the segregation of cell fate and cellular components in this lineage. Our preliminary data support a major role for FGF signaling in controlling b8.19/17 (posterior neural/neuromesodermal) vs b8.18/20 (dorsal midline tail epidermis) fates.
10:15 - 10:40am: Josephine Chandler, Associate Professor of Molecular Biosciences, KU
"Bacterial social behavior: cooperation, conflict and the evolution of quorum sensing"
Pseudomonas aeruginosa, an opportunistic pathogen, is a model for studying bacterial quorum sensing. The P. aeruginosa quorum-sensing regulator LasR contributes to virulence and increased resistance to several antibiotics such as tobramycin. Paradoxically, lasR-null mutants are common in isolates from tobramycin-treated patients. We hypothesized that these lasR-null isolates might have other mutations that result in lasR inactivation having the opposite effect on antibiotic resistance as is observed in laboratory strains. To test this hypothesis, we performed a laboratory evolution experiment. We grew P. aeruginosa populations in the presence of sublethal tobramycin concentrations and transferred the population to fresh medium every day. Variants from these populations rapidly developed tobramycin resistance. Inactivation of LasR in some variants further increased tobramycin resistance, consistent with our hypothesis that lasR mutations can increase antibiotic resistance in some backgrounds. These variants all harbored a point mutation in the gene encoding the translation elongation factor fusA1. We engineered the same fusA1 mutation in our laboratory strain. The fusA1 single mutant alone conferred a small increase in tobramycin resistance compared with the parent, but a lasR, fusA1 double mutant was significantly more tobramycin resistant. Our results support a model in which the consequence of a lasR-null mutation depends on the genetic background in which it emerges. Our work also offers a possible explanation for how lasR mutants emerge in infected patients and offer new insight into understanding quorum sensing evolution and biology.
10:45 - 11:10am: Michael A. Johnson, Associate Professor of Chemistry, KU
"Light-initiated Zn2+ Signaling in Parkinson's Disease Model Zebrafish"
The initial discovery four decades ago that mossy-fiber axons in the hippocampus release and take up free, ionic zinc (Zn2+) has led to a new field that examines how free and bound metals influence neuronal function. Metals in their free, ionic state (e.g., Zn2+, Cu2+, Mn2+) guide how neurons communicate, form memories, and process sensory input. Neurons release these metal ions by exocytosis, transiently influencing extracellular levels of neurotransmitters, such as dopamine, serotonin, and norepinephrine. Zn2+ dysregulation has been implicated in Parkinson’s disease (PD), the second most common neurodegenerative disease in the U.S. In this talk I will discuss work in which we have investigated Zn2+ signaling dynamics in ex vivo brains from zebrafish that model PD and controls. By combining caged Zn2+ photolysis with fast-scan cyclic voltammetry (FSCV), we found that transient Zn2+ application decreases dopamine uptake within milliseconds, while in brains from PD fish, Zn2+ application has no effect on uptake. Furthermore, Zn2+ photorelease did not affect the amplitude of dopamine release in control fish, but did in PD model fish. Treatment with TEMPOL, a free radical scavenger, reversed these effects. We speculate that reactive molecules produced in PD model fish covalently modify conserved Zn2+ binding sites, thereby interfering with the ability of Zn2+ modulate release and uptake.
11:10 - 11:20: Break
11:20 - 11:45am: Justin Blumenstiel, Associate Professor of Ecology & Evolutionary Biology, KU
"Genomic autoimmunity as a cost of small RNA-based genome defense"
Nearly all genomes carry selfish repetitive elements known as transposable elements (TEs) and these elements can cause DNA damage, mutation and chromosomal rearrangements. In response to this threat, systems of small RNA-based genome defense have evolved to limit the proliferation of TEs in the germline. However, as seen in other immune systems, there is a cost of genome defense when the distinction between self and non-self is muddled. piRNAs are a particular class of small silencing RNA that function in the germline to control TEs, but, under certain circumstances, genes can also become targeted for silencing. In this presentation, I outline recent work that describes the nature and consequences of this form of genomic autoimmunity.
11:50am - 12:15pm: Prajnaparamita Dhar, Professor of Chemical & Petroleum Engineering, KU
"Interface-induced protein particle formation in monoclonal antibody solutions subjected to stress"
Protein-based biotherapeutics, and specifically monoclonal antibodies (mAbs), have recently seen tremendous growth, given their tremendous ability to treat a host of diseases. Unfortunately, they are inherently unstable. Manufacturing, storage and administration of these protein-based biotherapeutics also involves exposure of the biotherapeutic to a wide variety of stresses, that further lead to protein instability and ultimately undesired protein particle formation (PPF). In this talk, I will discuss how coupling tensiometry techniques with microflow imaging techniques can be used to assess and predict the stability of several mAb formulations, both in the absence and presence of interfacial dilatational stress.