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Abstract: Proteostasis deficiency in ion channels leads to a variety of ion channel diseases called channelopathies, which are often caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking of mutant ion channels. We focus on proteostasis maintenance of gamma-aminobutyric acid type A (GABA_A) receptors, the primary inhibitory ion channels in the mammalian central nervous system. Numerous epilepsy-associated missense mutations in the receptor subunits predispose them to rapid ERAD, reduce their cell surface expression, and cause loss of their function. We aimed to use small molecules to adapt the proteostasis network in the ER to restore the surface trafficking and function of such mutant receptors. Our screening assay from a structurally diverse FDA-approved drug library identified lead compounds that enhanced the surface expression of a number of trafficking-deficient mutant receptors. Furthermore, patch clamping electrophysiology showed that these lead compounds restored their function on the plasma membrane. Mechanistic studies revealed that they reduced the degradation by attenuating the ERAD pathway. In addition, they enhanced the folding of the mutant subunits by enhancing their interactions with major GABAA receptors-interacting chaperones. Both ERAD inhibition and folding enhancement contributed to the improved ER-to-Golgi trafficking efficiency of the mutant receptors. These compounds hold the promise to be further developed to ameliorate idiopathic epilepsy resulting from excessive GABA_A receptor degradation.

Research:

Bio: David Mitzi is the Simon Family Professor at Duke University, with appointments to the Departments of Mechanical Engineering and Materials Science and ÌÇÐÄvlog¹Ù·½Èë¿Ú. He received his B.S. in Electrical Engineering and Engineering Physics from Princeton University (1985) and his Ph.D. in Applied Physics from Stanford University (1990). Prior to joining the faculty at Duke (2014), Dr. Mitzi spent 23 years at IBM’s Watson Research Center, where his focus was on the search for and application of new electronic materials, including organic-inorganic perovskites and inorganic materials for photovoltaic, LED, transistor and memory applications. For his final five years at IBM, he served as manager for the Photovoltaic Science and Technology Department, where he initiated/managed a multi-company program to develop a low-cost, high-throughput approach to deposit thin-film chalcogenide-based absorbers for high-efficiency photovoltaics. Dr. Mitzi has recently been elected a Materials Research Society (MRS) Fellow and named a Clarivate Analytics Highly Cited Researcher.

Abstract: Although known for over a century, organic-inorganic hybrid perovskites have received extraordinary attention recently, because of unique physical properties for the three-dimensional (3-D) lead-based systems, which make them outstanding candidates for application in photovoltaic and related optoelectronic devices. This talk will highlight the outstanding chemical flexibility of the more diverse 2-D perovskite family. As part of the discussion, the importance of structural dimensionality for determining semiconducting character, along with opportunity for both inorganic/organic structural components to play an active role in determining hybrid properties, will be emphasized. In addition to structural/electronic flexibility of the 2-D perovskites, the talk will explore the unique challenges for preparing high-quality films of these systems, and will present recent progress along several fronts, including melt-processing and resonant-infrared matrix-assisted pulse laser evaporation. Outstanding functionality combined with versatile and facile processing provide two pillars for future application and study of this family.

Abstract: The RNA-binding protein La-related protein 1 (LARP1) helps regulate the synthesis of ribosomes, the cellular machines that translate messenger RNAs (mRNAs) into proteins. Ribosomes themselves include many protein subcomponents that are critical for their functioning. The mRNAs that encode these ribosomal subcomponents, called 5’TOP mRNAs, are chemically distinct from most other mRNA molecules. LARP1 binds 5’TOP mRNAs, thereby controlling to what extent they are available for ribosome biosynthesis. Molecular dynamics simulations of LARP1 reveal that a portion of the protein near the 5’TOP-mRNA binding site is particularly flexible. Elevated LARP1 levels have been implicated in several cancers, so better understanding LARP1 dynamics could provide pharmacological insights that will lead to novel treatments.

Research:

Abstract: In an energy landscape with increased environmental concerns and reduced availability of fossil fuels, electrochemical systems will likely play a major role for automotive and grid-storage applications.  Our research strives to diagnose and overcome challenges related to electrochemical energy storage. We focus on mechanistic analysis that integrates both theory and experiment.  In this talk, I will discuss three applications of the aforementioned research approach ranging from the molecular to the device scale. In the first, we consider the origin of pH-dependent kinetics for hydrogen evolution and oxidation. Using single-crystal voltammetry and microkinetic modeling, we find that adsorbed hydroxide is a spectator at best and a poison at worst. The implications of this finding on electrocatalyst design are discussed. In the second application, we investigate the effect of inter-electrode communication on failure mechanisms in Li-ion batteries. Electrochemical characterization of surface films using redox mediators separates transport and kinetics to determine how nominally passivating films can selectively transfer charge. These results highlight the importance of a defect-free inorganic layer for a successful interface. Finally, we apply our approach to battery electrode design. We combine rheology with electrochemical analysis to determine the role of carbon microstructure in battery performance and reach the counter-intuitive conclusion that short-range electron transport is more limiting than either long-range conductivity or tortuous ion paths.

Maureen Tang joined the faculty of Chemical and Biological Engineering at Drexel University in fall 2014. She received her BS in Chemical Engineering from Carnegie Mellon University in 2007 and her PhD from the University of California, Berkeley in 2012. While at Berkeley, she received a NSF Graduate Research Fellowship, an NSF East Asia Pacific Summer Fellowship, and the Daniel Cubiciotti Student Award of the Electrochemical Society. Dr. Tang completed postdoctoral work at Stanford University and research internships at Kyoto University, the University of Dortmund, and DuPont. She is the recipient of a 2018 NSF CAREER award, the 2019 College of Engineering Early Career Research Award, and a 2018 Award for Excellence in Peer Review from the ACS PRF. Her research at Drexel develops materials, architectures and fundamental insight for electrochemical energy storage and conversion.

Abstract: Polymers have the potential to enhance the performance and safety of lithium-ion batteries as a result of their ability to simultaneously synthetically control often contradictory properties in a single material. Our focus centers upon redox active polymeric electrodes and functional polymer binders. However, the requirements for redox active polymers for energy storage are quite stringent; these include high doping level or capacity, stability, reversibility, conductivity, and practical application at high mass loadings. This talk will first introduce how electrochemically active polymers operate, specific challenges, and latest advances. Organic radical polymers are interesting for their rapid redox kinetics, high power, and radical-based chemistry. These polymers exchange electrons and ions by a process very different from conjugated polymers such as polyaniline. The origin of this process, as well as how it may be manipulated by adjusting the polymer backbone chemistry, are explored. Next, this talk will discuss polymer block copolymers that act as conductive binders, which is in contrast to normally insulating binders such as polyvinylidene fluoride. Finally, conjugated poly(fluorene-alt-naphthalene diimide) as an n-type polymer electrode for energy storage is examined. As we look to the future, polymers may be the enabling factor towards unconventional batteries, possibly merging plastic electronics with plastic power to form a new paradigm.

Bio: Jodie L. Lutkenhaus is the William and Ruth Neely Faculty Fellow and Professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University. Lutkenhaus received her B.S. in Chemical Engineering in 2002 from The University of Texas at Austin and her Ph.D. in Chemical Engineering in 2007 from Massachusetts Institute of Technology. Following a postdoctoral position at University of Massachusetts Amherst, she joined the faculty at Yale in 2008. In 2010, she moved to Texas A&M University and was promoted to Associate Professor in 2015. Current research areas include polyelectrolytes, redox-active polymers, energy storage, and anti-corrosion coatings. She has received recognitions including World Economic Forum Young Scientist, Kavli Fellow, NSF CAREER, AFOSR Young Investigator, 3M Non-tenured Faculty Award. She is the 1st Vice Chair of the AICHE Materials Engineering & Sciences Division. She serves on the Editorial Advisory Boards for ACS Macro Letters, Macromolecules, ACS Applied Nano Materials, Molecular Systems Design & Engineering, and Materials Today.  Lutkenhaus is the Deputy Editor of ACS Applied Polymer Materials.

Abstract:

Insulin and the blood-brain barrier (BBB) interact in at least two distinct ways that are related to cognitive impairment.  Insulin plays important roles in cognition, neurogenesis, and CNS mediated metabolic regulation. Yet nearly all of the insulin is produced by the pancreas and dependent on transport by the BBB.  Evidence suggests that impaired insulin transport at the BBB and resistance within the brain occur in Alzheimer’s disease.  Additionally, the BBB deteriorates with the hyperglycemia of diabetes.  This talk will briefly explore these two mechanisms. After a general overview of BBB and insulin transport, mechanisms by which hyperglycemia through oxidative stress results in pericyte death and BBB disruption will be discussed.  I will then discuss CNS insulin resistance and therapeutic approaches to overcoming it.

SomaLogic has developed a novel class of chemically-modified aptamers, called SOMAmer Reagentsâ„¢.   Aptamers are short ssDNA molecules, which are identified through an in vitro evolution process called SELEX, that bind protein targets with affinities approaching that of antibodies.   Modification of canonical ssDNA aptamers with amino acid side chains or aromatic rings further enhances their protein binding capability by allowing evolution of stabilizing hydrophobic-hydrophobic interactions not possible for the natural CAGT bases.   Examples of the synthetic chemistry and biomedical applications of SOMAmer reagents will be presented.