Friday, October 18, 2013
Pharmaceutical Applications of Metabolomics
The metabolome, or the total compliment of small molecules in a living system that includes endogenous andintroduced species, reflects the overall global biochemical state of an organism. Changes in the functionalgenome, transcriptome and proteome are closely tied to changes in the metabolome. Metabolomics (ormetabonomics) is the comprehensive measurement of the metabolome and how it changes in response to external stressors. In Pharmaceutical R&D, this information can be used to deduce the relationshipbetween a perturbation (such as disease or pharmacological intervention to disease) and the affectedbiochemical pathways, yielding mechanistic information and biomarkers that report upon the perturbation. These biomarkers can in turn inform and accelerate the discovery of safe and efficacious drugs. This talk will provide a background on the technology and present several examples of how it has been employed in mainstream pharmaceutical R&D.
Michael D. Reily, Ph.D. joined Bristol-Myers Squibb in September of 2007 as a Research Fellow in Bioanalytical and Discovery Analytical Sciences. He currently manages the Discovery Analytical Sciences NMR group and is coleader of the Applied and Investigative Metabolomics (AIM) matrix team. Dr. Reily received his Bachelor of Science Degree in Chemistry from the University of West Florida in Pensacola and his Ph.D. in Bioinorganic Chemistry from Emory University in 1986. During his graduate work, Dr. Reily became interested in the application of high resolution NMR spectroscopy to answer structural questions about biomolecular interactions with drugs, and he pursued this interest in postdoctoral with John Markley in the Biochemistry Department at the University of Wisconsin, Madison. In 1988, he came to Ann Arbor to the then Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company and has applied NMR spectroscopy to drug discovery and development in areas of medicinal chemistry, protein and nucleic acid structure determination and metabolite structure elucidation. His most recent career focus has been on the application of NMR and mass spectrometry-based metabolomics to study mechanistic toxicology and pharmacology and identify associated biomarkers. Dr. Reily is a member of the American Chemical Society and is author or co-author on over 80 peer-reviewed journal articles and book chapters.
Self-Assembled Block Copolymer - Nanoparticle Hybrids
Ionic fluids consist of a collection of dissociated ions. Notable examples are room temperature ionic liquids (RTILs) and molten alkali halides. This class has recently gained considerable attention, mainly due to the potential applications of RTILs in nanotechnology, energy storage and chemical processing. At the same time, studies on theoretical models continue to provide insight into the behavior of electrolyte solutions and colloids. This field has greatly benefitted from different types of molecular simulation due to the ability for one to use this tool to relate the macroscopic properties of a system to the underlying microscopic interactions. One type of simulation, called Monte Carlo, employs statistical thermodynamics to generate different configurations of molecules in order to calculate the thermophysical properties of a given system. In this presentation, we first describe how MC simulations are used to compute bulk and interfacial properties of interest. For the bulk behaviors, we present the vapor and liquid phase properties of different RTILs having a wide variety of structures and inter-ionic interactions. We examine thermodynamic properties, such as the saturated densities, vapor pressure, and enthalpy of vaporization, as well as metrics that describe the structure molecules adopt in the liquid and vapor phases. Regarding interfacial phenomena, we consider how different ionic fluids wet a particular solid surface. Here, we use a simple model for ionic fluids to systematically understand the influence of electrostatic interactions on wetting properties. Results are presented to show how the strength of the interaction between the fluid and solid as well as the system temperature affect the properties and microscopic structure of the fluid near the surface.
Engineering Biomimetic Microenvironment for Vascular Grafts
Cardiovascular disease (CVDs) is the leading cause of death in the developed world. Although the autologous replacement remains the golden standard, the limited supply and the pain caused by multiple surgeries necessitate the development of tissue engineered vascular constructs (TEVs) as alternatives. Previously, our group has made significant progress in engineering vascular grafts using natural materials such as fibrin and small intestine Submucosa (SIS). These grafts have been successfully implanted into an ovine animal model, where they remained patent for several months post implantation. However, certain challenges still remain such as diffusion limitations of growth factors through the vascular wall, heterogeneous distribution of cells, uneven collagen deposition and lack of elastin fibers. In order to address these issues, we developed biomimetic strategies to mimic the chemical and mechanical microenvironment of native arteries. Because supplement of TGF-1 has been shown to promote myogenic differentiation and extracellular matrix (ECM) deposition in TEVs, we first engineered a fusion between TGF-1 and a FXIII substrate peptide, which covalently anchored the fusion protein into fibrin during polymerization to simulate the local delivery of TGF-1 in native vessels (Fig. a). Because mechanical stimulation also plays important roles in vascular tissue, we developed a 24-well based bioreactor (Fig. b) in which vascular grafts were cultured around a distensible mandrel in the middle of each well to mimic the cyclic pulsatile stimulation in vivo. TGF-1 was either conjugated to fibrin or supplied in the culture medium and the fibrin-based constructs were cultured statically for a week followed by either another week of static culture or a week of cyclic distention. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results suggest that this two-prong biomimetic approach, immobilizing TGF-1 in the 3D scaffold and controlling the mechanical microenvironment, can significantly improve cell distribution (Fig. c), ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings suggest the importance of biomimetic strategies to engineer the tissue microenvironment for vascular grafts and for other tissue constructs as well e.g. cartilage, tendon or cardiac tissue, where TGF-1 and mechanical loading play critical roles.
Winners of The Poster Competition