Our long-term objective is development and application of methods for relating function, design and significance of integrated biological systems to their underlying molecular determinants. Most of the ideas derived from earlier work on integration and organization would have to be termed metaphorical since it was not until recent years that the underlying moleculare basis was uncovered. During the past few decades the success of moleculare biologists in discovering the biochemical and genetic compontents of biological systems led to at least a partial elcipse of interest in the integrated behavior of the intact system. However, largely as a result of this success, we are now in a position to examine the integrated behavior from an informed molecular perspective. This proposal is concerned with five specific aims; namely, anaylsis of (1) accuracy and energy cost of proofreading in biosynthetic networks; (2) biochemical control involving precursor activation, a mechanism uniquely associated with amphibolic pathways; (3) gene control involving termination of transcription and gene control involving the switching of regulatory mechanisms; (4) higher-order biochemical networks as implcated in protein and RNA processing; and (5) DNA sequences involved in nonhomologous recombination, a mechanism potentially important for the switching of genetic regulatory systems. The methodology emphasized in our approach will be mathematical systems analysis and computer analysis because of their unique ability to systematically relate integrated function and design of complex biological systems to their molecular elements. The general outline for the analysis in each case is as follows: Specific models based on known molecular data are formulated; the integrated behavior of these models is analyzed and compared according to several different criteria for functional effectiveness; the results of the analysis are interpreted in terms of optimal designs for specific functions; and, finally, the biological significance of the results is addressed and predictions are made for experimental testing. The projectws of this proposal are likely to contribute to our understanding of normal processes such as homeostasis, growth, development and aging, and of pathological manifestations such as metabolic diseases, developmental abnormalties and cancer.
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