Dennis Miller, PhD - US grants

The long-term goal of the proposed research is the identification and characterization of modes of gene expression unique to mitochondria. These studies define the possible mechanisms of gene expression and provide clues to the origin of genetic information. A unique step in mitochondrial gene expression has been identified in the mitochondria of the myxomycot, Physarum polycephalum. The genetic information for the alpha subunit of the ATP synthase complex is produced by insertion of cytidine residues at specific sites in the mRNA, a process termed RNA editing. The specific goal of this proposal is to determine the mechanism, extend and role of the RNA editing in mitochondrial gene expression in Physarum. The mechanism of RNA editing will be studied through the development of an in vitro editing system. Mitochondrial fractions having enzymatic activities associated with RNA editing will be purified and characterized. Mitochondrial nucleic acids will be screened for sequences which could serve as a template for this process, and the sequence of the mRNA will be systematically altered in order to determine its role in editing specificity. To determine the extent of RNA editing in Physarum mitochondria, additional genes on the mitochondrial DNA will be identified and screened to determine whether RNA editing is required for their expression. Finally, the role of RNA editing in the control of mitochondrial gene expression will be explored. Editing efficiencies during the life cycle and at the onset of plasmodial senescence will be compared, to determine if there is a correlation between RNA editing and mitochondrial activity in Physarum.

Pre-clinical research from our laboratory suggests that LOB or its synthetic derivatives have potential as effective pharmacotherapies for METH abuse. Our previous research indicates that LOB reduces DA available for reverse transport by DAT, by redistribution of DA storage via a direct interaction at VMAT2. However, much of this research has focused on the acute in vivo presentation of LOB or in vitro assessment of the effects of LOB in rats that were never exposed to METH. Given the significant changes in DA neuron functioning with repeated METH treatment and the induction of drug craving, it is important to assess the effectiveness of LOB at VMAT2 and DAT in METH-sensitized animals. The present research will determine whether, contrasted to saline-treated animals, repeated METH administration alters LOB-induced DA utilization in vitro as indicated by an increase in DA and dihydroxyphenylacetic acid (DOPAC) overflow from superfused striatal slices. Concentrations of LOB that do not inherently increase DA or DOPAC overflow will then be used to determine whether LOB inhibits METH-evoked DA overflow from striatal slices from repeated METH and saline chronically pretreated rats. To ascertain potential repeated METH-induced alterations in LOB action, effects of LOB on VMAT2 and DAT following repeated METH administration will be determined. Thus, these repeated METH pre-exposure studies will provide the necessary basis for LOB to be considered as a novel therapeutic agent for the treatment of METH abuse.

This project addresses critical research needs in the rapidly developing area of catalytic conversion of biorenewables. Organic acids produced via fermentation constitute an important class of renewable resource-derived compounds; they are made in large quantities from biomass and can be converted into a variety of building blocks for pharmaceuticals, foods, polymers, solvents, and other products. The research will characterize organic acid adsorption and hydrogenation on heterogeneous metal catalysts in an aqueous environment. The reaction and adsorption studies to be conducted with organic acids and combinations of acids with other species will develop a better understanding of binding strengths and reactivities of organic acids and their reaction products on different metal catalysts, thus providing a foundation for ultimately tailoring catalyst properties for hydrogenation of specific organic acid substrates. Additional aspects of the work will clarify key issues such as the role of water on the catalyst metal, the effect of poisons such as CO, and retention and generation of chirality in the product species. Further, because hydrogenation and dehydrogenation share chemical pathways, this work has implications for hydrogen generation from biomass as a clean energy source. From an environmental standpoint, heterogeneous hydrogenation over metal catalysts in water allows easy catalyst separation and reuse, avoids organic solvents, and greatly reduces waste generation in comparison to use of homogeneous catalysts or traditional hydride reagent chemistry. This "green" hydrogenation pathway thus represents a primary class of enabling technologies needed for the "biomass refinery" of the future. Finally, this effort supports the larger mission of educating the next generation of scientists, who will be responsible for producing our nation's chemicals and fuels from renewable, sustainable resources.

This workshop will identify US research capabilities, needs, and strategies for using catalysis to produce value-added chemical from biorenewable feedstocks. The goals of the workshop are: 1) to identify and communicate critical needs for building scientific and engineering capabilities in catalysis to convert biorenewables to value-added products; 2) to assess the current state of heterogeneous and homogeneous catalysis and biocatalysis research for conversion of biorenewables; 3) to identify curricular and workforce needs to prepare engineers and scientists for a biorenewables-based chemicals industry; 4) to develop and prioritize goals and directions for the development of effective catalysts and catalytic process for biorenewables conversion, including the integration of chemical and biochemical catalysis in the future "biorefinery."

The workshop will assist in developing a community of researchers with diverse professional and individual backgrounds for this new area of catalysis. Workforce requirements for a biobased chemicals industry will be addressed including new educational initiatives. Curricular issues for chemical engineering and chemistry departments will be addressed. Participants will include faculty, industrial leaders, and national laboratory researchers.