BTBA x TTBA Webinar 05

Sat, Mar 21, 1:00-3:00 PM, 2015

Austin | UT Austin, BME 1.112 Houston | BCM M319.06 Dallas | UT Southwestern NA5.218

Dissecting the evolution of cohesin paralogs in Saccharomyces cerevisiae

Yu-Ying Hsieh PhD Candidate, Harvard MCB

FcRn tissue expression analysis - why it matters to protein therapeutics

Yao-Yun Fan Postdoctoral Fellow, Pfizer


Yu-Ying Phoebe Hsieh is a PhD candidate at Harvard University, Molecular, Cellular and Organism Program. In Dr. Andrew Murray’s lab, Yu-Ying’s research focuses on the role of gene duplication in the emergence of new cellular processes. In this seminar, she will present her work on “Dissecting the evolution of cohesin paralogs in Saccharomyces cerevisiae”.


Abstract

How do the duplication of a gene and divergence of the protein it codes for play a role in the emergence of a novel cellular process? By focusing on the cohesin protein complex, a critical player in chromosome segregation, my project aims to identify the molecular mechanism required for two paralogs of kleisin, a subunit of the cohesin complex, to perform specialized functions either in mitosis or meiosis in the budding yeast, Saccharomyces cerevisiae. First, I will identify the parts of kleisin that determine the mitotic and meiotic function of cohesin by swapping the known protein domains between kleisin paralogs. Second, I will ask how strongly the various functions of cohesin are conserved among kleisin orthologs. Third, I will experimentally evolve a kleisin protein to examine the possible evolutionary paths leading to functional changes. This evolution experiment will offer new insights into molecular evolution by distinguishing between two hypotheses about how kleisin paralogs become specialized in different cellular contexts: 1) Gene duplication relaxes selection on the function of the cohesin complex, allowing individual kleisin paralogs to specialize for mitosis or meiosis, 2) Gene duplication is essential because the roles that kleisin plays in mitosis and meiosis are mutually incompatible. Dissecting kleisin's molecular evolution will give us a coherent account of protein specialization from protein sequence to molecular function to cellular roles in chromosome segregation. In this talk, I will present my preliminary data and current work to address the above questions.


Dr. Jessy Yao-Yun Fan is currently a postdoctoral fellow at Pfizer Worldwide Research & Development. She joins Pfizer as a postdoctoral fellow after finishing her PhD at ETH Zurich, Switzerland. Her research focuses are mass spectrometry-based protein quantification and glycoprotein characterization, two important areas for the development of protein therapeutics. Jessy will tell us about “FcRn tissue expression analysis - why it matters to protein therapeutics”. This project aims at targeting proteins with pharmaceutical interests from tissues in order to quantitatively reflect therapeutic dosing response at the actual site of action. This is a critical and sensitive step to influence the success of translational pharmacokinetics.


Abstract MNeonatal Fc receptor (FcRn) is the homeostatic receptor responsible for the serum half-life of endogeneous IgG by protecting it from lysosomal degradation. Understanding systemic FcRn tissue expression is important to predict and design the half-life of therapeutic antibodies and Fc-coupled biologics. Homozygous Tg32 (Tg32) are human FcRn knock-in transgenic mice under the control of human endogenous promoter. A strong correlation of drug clearance in Tg32 and humans has been demonstrated. Building an FcRn tissue expression profile in Tg32 is enabled by a workflow which includes development of an innovative tissue preparation procedure linked to novel online peptide immuno-affinity LC-MS/MS method in order to bypass challenges of membrane protein analysis. Current results showed tissue extraction efficiency was between 95.5-97%. FcRn expression in liver was found to be 5 times higher than in lung, corresponding to high pmol of FcRn per gram of tissue. This approach has quantitatively confirmed FcRn expression in vascular endothelial cells and hepatocytes qualitatively reported in literature. Ongoing analysis of FcRn data from kidney and skin will facilitate understanding of FcRn contributions to the clearance rate of antibodies. A complete FcRn tissue expression profile will increase the accuracy of physiologically-based pharmacokinetic dose prediction of protein therapeutics, which is the foundation of translating pharmacokinetic data from preclinical model system to humans.

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