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Division of Pharmacology, Physiology, and Biological Chemistry

Description:

Research related to the actions of therapeutics, including anesthetics, and the development of biotechnological methods for their production and investigation. Research on cell signaling molecules and signaling intermediates, particularly those related to G-protein coupled receptors. Research in the field of glycomics, especially tool and methods development for this emerging field. Research on pain management as it relates to anesthesia and the perioperative period. Research on responses to traumatic injury, including burn injury, and methods to mitigate these responses. Research on wound healing and tissue repair. Research on the causes and treatments for common complications of critically ill patients (sepsis, systemic inflammatory response syndrome, multiple organ failure), especially directed towards the role of the inflammatory and innate immune responses. Research leading to new knowledge of physiological functions at the molecular, cellular, and organ systems levels. Research on the structure, function, and biosynthesis of cellular components and cellular metabolism, bioenergetics, and mechanisms of enzyme action, regulation, and inhibition. Research leading to the synthesis of new chemical entities or development of new chemical methods to probe biological phenomena or to alter the behavior of biological systems. Examples include, but are not limited to:

A. Methods for isolation, characterization, and production of natural and bio-engineered products.

1. Metabolic engineering for the production of biochemicals through genetic and bioengineering manipulation of biosynthetic pathways.

2. Biosensors for use both in vivo and in vitro in process engineering.

3. Methods for rapid purification of natural products.

4. Methods for rapid determination of natural product structures.

5. Methods for efficient production of natural products.

6. Universal expression systems for heterologous production of natural products.

B. Development of innovative synthetic chemistry.

1. Catalytic asymmetric methods and methods for large-scale synthesis.

2. New methods applicable to combinatorial library construction, design, analysis, and/or handling.

3. Improved methods for preparation of isotopically labeled amino acids, peptides, proteins, and prosthetic groups, and therapeutic agents.

C. Development of enzymes, catalytic antibodies, ribozymes, artificial enzymes, and host molecules as drugs or synthetic tools.

1. Synthesis of suicide substrates, affinity labeling agents, and transition state analogs as potential therapeutic agents.

2. New enzyme assays to reduce the reliance on radio-isotopes.

3. General approaches for high throughput screening.

D. Isolation, characterization, and development of factors involved in tissue repair and wound healing, i.e., growth factors. Tissue engineering. Development of artificial skin and skin replacements.

E. Development of strategies, methods, or molecular based treatments to improve the speed and outcome of wound healing or to induce regeneration as a substitute to normal wound healing.

F. Metabolomics/metabonomics of injury and/or critical illness.

G. Improved systems for collection, processing, and analysis of real time physiological data from injured or critically ill patients. Application of systems biology or complexity theory approaches towards understanding the physiology of injured and critically ill organisms.

H. Development of tools, software, algorithms, etc. needed to link clinical, demographic, physiological, genomic, proteomic or other datasets of injured or critically ill organisms.

I. Development of strategies, methods, or new technologies to improve the delivery, monitoring, safety and efficacy of anesthesia.

J. Research to improve drug design.

1. Methods for understanding of structure-activity relationships.

2. Mechanisms of drug-receptor interactions.

3. Development of molecular diversity libraries.

K. Research to improve drug bioavailability by improved understanding of factors that influence absorption, metabolism, transport, or clearance of therapeutics and underlying mechanisms.

1. Determination of structure-activity relationships for drug metabolizing enzymes.

2. Determination of structure-transport relationships for active and passive transport of drugs and metabolites.

3. Research on drug transporter structure, function, and regulation.

4. Development and validation of models for prediction of drug bioavailability and metabolism in humans.

5. Research on inter- and intra-individual differences in bioavailability.

6. Methods to improve sensitivity, accuracy, speed, and simplicity for measurements of drugs and their metabolites in complex biological matrices.

L. Application of pharmacokinetic and pharmaceutical principles to the study of large biomolecules, such as proteins, polypeptides, and oligonucleotides.

M. Development of novel targeted delivery systems for both conventional drugs and large molecules.

N. Research to discover, detect, and understand the genetic basis of individual differences in drug responses.

1. Identification of polymorphisms in human drug receptor and drug metabolizing enzymes.

2. Development of laboratory-based and computational approaches for pharmacogenetic and pharmacogenomic mechanistic studies.

3. Development of statistical analysis methods related to research in pharmacogenomics.

4. Development of genotyping and phenotyping tests to support research in pharmacogenomics.

5. Development of proteomic and metabolomic methodologies related to research in pharmacogenomics.

6. Creation of appropriate databases, specimen, and cell culture collections to support research in this area.

O. Development of novel in vivo and in vitro methods to predict toxicities of pharmacologic agents.

P. Development of differentiated hepatic cell lines from human stem cells that are equivalent to adult hepatocytes to characterize metabolic profiles of pharmacological candidates by phase 1 and 2 enzymes.

Q. Development of bioinformatic, mathematical, and/or computational approaches/resources and/or pharmacokinetic modeling programs which utilize ADME parameters of drugs and pharmacogenomic information of individual patients or patient populations to reduce adverse drug reactions in individual patients.

R. Development of ontologies and modules useful for combining and mining databases containing genotype and phenotype information in order to discover correlations for drug effects, either therapeutic or adverse.

S. Development of methods and tools for the field of glycomics including but not limited to:

1. Development of carbohydrate specific databases as well as informatics tools to mine carbohydrate data bases.

2. Development of new facile methodologies to rapidly synthesize and expand defined carbohydrate libraries, especially those applicable for screening for glycomic biomarkers, assessing carbohydrate protein interactions, and development of glycan arrays.

3. Development of linker methods for carbohydrates.

4. Development of methods for exploring glycan-protein, glycan-lipid, and glycan-glycan interactions.

5. Development of well characterized commercial sources of glycosyltransferases and glycosidases that can be used as research tools by the scientific community.

6. Development of methods for high throughput structural analysis of the glycoconjugates of proteins and lipids.

7. Development of defined antibodies as tools for the field of glycomics.

T. Development and application of methods and materials for the elucidation of membrane protein structures at or near atomic resolution.

1. Novel vector and host cell systems for over-expression of membrane proteins, in both unlabeled and isotopically labeled forms.

2. Novel and high purity detergents and non-detergent solubilization agents for the purification and crystallization of membrane proteins.

3. Apparatus to facilitate crystallization and manipulation of fragile crystals for data collection.

4. Reagents for heavy atom derivatization of membrane protein crystals.

U. Development of high-throughput methods for sequencing and resequencing of mitochondrial genes and relevant nuclear genes and for proteomic and/or functional profiling of mitochondria in diagnosis of mitochondrial diseases.

V. Development of methods to create site-directed and knock-out mutations of mitochondrially-encoded genes in higher eukaryotic cells and experimental animals.

W. Development of new metal ion chelators and other tools to probe and/or alter the localization and concentration of metal ions in cells and in whole organisms. Research to exploit metal metabolism and metal-regulated cellular control and cell-cell signaling processes to probe and/or alter cell function. Research to develop investigational and therapeutic applications of metal-complexes and to understand the factors governing their pharmacology and toxicology.

X. Development of high-throughput methods and strategies to characterize the function of proteins and enzymes and/or define the functional interrelationships of proteins and enzymes.

Y. Development of research tools to promote scientific collaboration in any of the above areas of research. For example, applications software for secure peer-to-peer networking to facilitate the exchange of scientific data and research materials or to construct a searchable distributed database.

Z. Development of tools to characterize oxidative stress and oxidative stress related molecules (NO, peroxynitrite, hydrogen peroxide, lipoxidation products modified proteins, DNA modifications, etc.) including the extent and/or localization (by organ/tissue/cell/organelle) of oxidative stress.

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