Samuel Smith - US grants

Atherosclerosis, a multifaceted disease, is the result of metabolic aberration(s) in the arterial wall aggravated by physiological stressors set up by life style risk factors. The hallmark feature of early atherosclerosis is accumulation of esterified cholesterol in foam cells originating from either monocytes migrating into the arterial wall or from constituent smooth muscle cells. Genetic factors governing susceptibility to atherosclerosis are believed to reside at least in part at the level of the arterial wall, and the long-term goals of this laboratory are: 1) to determine the mechanism(s) responsible for pathogenic accumulation of cholesteryl esters within arterial smooth muscle cells; and, 2) to describe genetic factors controlling these mechanisms. Use of the atherosclerosis-susceptible White Carneau and -resistant Show Racer pigeon model system is advantageous for these goals since: foam cells are formed from smooth muscle cells in the naturally-occurring disease; genetic susceptibility/resistance resides in the arterial wall; and, life-style risk factors are not involved. Once this "simplest-case" scenario for atherogenesis -- i.e. metabolic abnormality in vascular smooth muscle cells -- is understood, other components of the pathogenic process (eg., lipoproteins, endothelial damage, monocyte infiltration, etc.) can be more completely evaluated. Early differences in glycosaminoglycan (chondroitin-6-sulfate) accumulation and intracellular distribution of B-glucuronidase (greater localization in endoplasmic reticulum) precede cholesteryl ester accretion in lesion-prone areas of susceptible aortas. In the endoplasmic reticulum, B-glucuronidase is bound to the protein egasyn, an esterase which occurs both bound and free in this organelle. Egasyn possesses much greater lipase (cholesteryl esterase?) activity when free, and its activity may be regulated by the amount of B-glucuronidase present in the endoplasmic reticulum. Thus, the specific aims are: 1) to describe changes in cholesterol metabolism produced by chondroitin-6-sulfate (C-6-S) added to cultured aorta smooth muscle cells from atherosclerosis-susceptible and atherosclerosis-resistant pigeons; and, 2) to define alterations in B-glucuronidase/egasyn distribution produced by C-6-S in the same system. Radioactively labeled metabolites (acetate, cholesterol) will be added to cultures in the presence or absence of C-6-S and the appearance and/or disappearance of cholesteryl esters in cells from both breeds monitored as a function of time. Cells will also be analyzed for the total B-glucuronidase activity and for the proportion of bound and unbound egasyn as a function of treatment with C-6-S.

The object of this workshop is the evaluation of underwater vehicle technology through the use of competitive scenarios. The workshop will bring together the experience and knowledge of autonomous underwater vehicle technology with the experience that has been gained through the International Submarine Race program to foster innovation and technology development through competition. The subject is sufficiently complex and has attracted a very large degree of interest so that a workshop of invited experts is the best method to advance the concept to practice. This approach will be employed to examine the process of utilizing competition to foster and evaluate technical advances and as a result to develop scenarios with which to characterize, evaluate and advance the state of the art of Autonomous Underwater Vehicles. The results of the workshop will provide the basis for competition based programs for technology enhancement and evaluation in the future.

9309960 Smith This is the first-year funding of a three-year continuing award. This research addresses the task of finding the optimal control policy for complex, nonlinear, and uncertain systems, given a set of control objectives. The majority of effort so far in intelligent control systems has been focused on implementation or function approximation for complex, nonlinear, and uncertain systems. It is assumed a priori that the given training information best satisfies the control objectives without a direct attempt to find the optimal system control policy with respect to the control objectives. Conventional optimal control methods are either limited to systems that are amenable to mathematical analysis or else involve enormous amounts of computation in the form of dynamic programming. Intelligent control approaches that address the task of determining the optimal control policy use the same basic strategy as dynamic programming, only in less structured form. This includes Back- propagation Through Time (BTT) methods and systems that employ reinforcement learning or adaptive critics. This research project uses a computationally efficient means of dynamic programming based on a cell state space approach that makes it possible to do multiple iterations of the algorithm in realistic time scales. These methods will be applied to the six-degree-of-freedom flight control of Autonomous Underwater Vehicles under development at Florida Atlantic University. One application of these AUVs is a joint effort between the University of South Florida's Marine Science Department and FAU to perform a set of long range oceanographic surveys in the Gulf of Mexico to determine bottom composition and water quality. Because underwater vehicles can move freely in three dimensions in relatively uncluttered environments, the immediate potential for valuable contributions by autonomous robotic systems may be even greater in the ocean than on land.

[unreadable] DESCRIPTION (provided by applicant): Atherosclerosis in the susceptible pigeon has many similarities to human atherosclerosis including the geographical localization of lesions in the vascular tree, altered endothelial and smooth muscle cells, and the progression of lesion development. The pigeon model is unique in that susceptibility to spontaneous aortic atherosclerosis in White Carneau (WC) pigeons is due to a single gene and it follows an autosomal recessive pattern of inheritance uncomplicated by any known risk factors. Human atherosclerosis is a complex, multifactorial disease, in contrast to the pigeon model, which represents a simplest-case system suitable for defining the genetic basis for lesion development. Susceptibility to atherosclerosis in the pigeon resides at the level of the arterial wall and is manifested as lesions at the celiac bifurcation of the aorta. However, the mechanism responsible for lesion development is not known, and no studies have been conducted to identify the gene or gene product responsible. Since aortic smooth muscle cells cultured from these pigeons resemble smooth muscle cells in the lesion area both morphologically and biochemically, they will be used as a convenient, easily extractable source of genetic materials for this study. Pools of differentially expressed genes will be isolated by comparing cDNA produced from mRNA expressed in aortic cell cultures from susceptible WC pigeons with that produced from resistant Show Racer (SR) pigeons through a process called Representational Difference Analysis. This technique enriches for isolated genetic material from differentially expressed mRNA, increasing the probability of finding the genetic difference related to atherosclerosis by decreasing the size of the gene pool which must be examined. Differential expression of candidate genes will be verified by Southern blots against cDNA from both breeds and Northern analyses against mRNA extracted from the cultures. The final test for relevancy of the isolated gene or genes will be Southern blots against genomic DNA from Both breeds. The candidate genes will be cloned and sequenced, and the products or functions deduced from existing genomic databases. [unreadable] [unreadable]