Chris Gamblin, Ph.D., Associate Professor, Department of Molecular Biosciences (KU-L)
Neurodegenerative disorders that contain significant pathology of the microtubule-associated protein tau pose a significant burden on society and are predicted to grow in numbers as the population above the age of 65 continues to increase. This presentation will describe the current research being done in the Gamblin lab to understand the molecular mechanisms of tau toxicity in vitro and in model organisms in an effort to identify potential therapeutics.
Stuart Macdonald, Ph.D, Associate Professor, Department of Molecular Biosciences (KU-L)
“The Genetic Basis of Xenobiotic Resistance in Drosophila”
Living organisms are constantly exposed to an array of toxins in their environment and diet. If behavioral avoidance of these xenobiotics is not possible, and they are ingested, animals initiate a detoxification response to metabolize toxins into less harmful compounds ready for excretion. The transcriptional response to xenobiotic challenge involves a suite of detoxification enzyme-encoding genes, including cytochrome P450 monooxgenases, glutathione S-transferases, and so on. However, the precise mechanism of detoxification, and the role of genetic variants in contributing to variation in the detoxification response, is less clear for the majority of drugs. The Macdonald lab is interested in genetically dissecting the regulation of the detoxification response in the model organism Drosophila melanogaster. We have employed a novel genetic mapping technology - the Drosophila Synthetic Population Resource (DSPR) - to identify those loci contributing to variation in xenobiotic resistance. The DSPR is composed of over 1,600 genotyped Recombinant Inbred Lines (RILs) derived from a pair of multiparent, advanced generation intercross populations, and is capable of resolving Quantitative Trait Loci (QTL) to short genomic intervals. In addition, because the DSPR was founded by a total of 15 strains, allelic and phenotypic diversity in the mapping panel is high, allowing a robust picture of the complexity of the genetic architecture of the trait. Using a range of high-throughput phenotyping screens we have identified QTL that contribute to genetic variation for resistance to various drugs, such as nicotine and caffeine. Coupled with RNAseq experiments, we have identified a series of candidate genes, many of which are members of classic detoxification pathways, that are likely to causally contribute to xenobiotic metabolism.
Wolfram R. Zückert, Ph.D., Associate Professor, Director, Infectious Diseases Module (ID, CORE 850)Chair, Education Council, Microbiology, Molecular Genetics and Immunology (KUMC)
“Architecture and Biogenesis of a Spirochetal Host-Pathogen Interface”
Spirochetes are diderm bacteria that, like Gram-negatives, are enveloped by two membranes separated by a periplasmic space. Yet, the interfaces of the three clinically relevant spirochetal genera with their hosts differ significantly. Leptospira interrogans, which causes the world's most common zoonosis, is probably most similar to Gram-negative bacteria in displaying abundant lipopolysaccharide molecules on its surface. The syphilis agent Treponema pallidum, on the other hand, is considered a stealth pathogen due to its dearth of surface-exposed moieties. Belonging to the third clinically important spirochetal genus, Borrelia burgdorferi is the agent of Lyme disease, the most common vector-borne infectious disease in the Northern hemisphere. Its host-pathogen interface is unusual in that it is dominated by peripherally anchored surface lipoproteins that function, e.g., as adhesins and anti-complement factors. Our work has focused on both the architecture and biogenesis of this interface by defining structure-function relationships of Borrelia surface lipoproteins and by deciphering their secretion pathways. We have shown that (i) surface lipoprotein localization determinants commonly localize to intrinsically disordered N-terminal tether peptides, (ii) translocation through the outer membrane (OM) requires an at least partially unfolded lipopeptide, (iii) accordingly, dimer lipoproteins assemble into their final quaternary fold after reaching the bacterial surface, and (iv) translocation through the OM can be initiated by an unfolded C-terminus. Preliminary studies also suggested that at least one of the predicted inner membrane Lol pathway orthologs is not directly involved in surface lipoprotein localization. We therefore hypothesize that surface localization requires maintenance of a translocation-competent intermediate, likely by interaction with a periplasmic holding chaperone, which may work in concert with a so far unidentified OM lipoprotein translocon. Current studies focus on the identification of these pathway components by a suppressor screen and the capture of secretion intermediates by a bimolecular trapping approach. Taking advantage of known Borrelia surface lipoprotein structures and functions, we are also exploring the role of particular surface lipoprotein domains in the infectious cycle and pathogenesis of Lyme disease.