New Horizons in Therapeutics – serie

This volume focuses on recent developments in our understanding of selected adhesion processes that may offer new approaches to developing therapeutics for a variety ofdiseases. The volume first introduces the molecules involved in key adhesive processes, then describes the biological consequences of several adhe- sive interactions, and closes with a description of the initial therapeutic ap- proaches to antagonizing. adhesion. These papers were originally presented at the SmithKline Beecham Pharmaceuticals Seventh U. S. Research Symposium held in Philadelphia in October of 1992. ofacell to asurface. In its simplestsense, cellularadhesion is the adherence The cells of interest in the context of this volume are bacterial and mammalian, with an emphasis on leukocytes; surfaces can be other cells and tissues (such as bone), matrix proteins, or inanimate objects such as in-dwelling medical devices and catheters. Interaction between adhesion molecules usually results in a spe- cific biological response. Adhesion is a form ofcellularcommunication, and represents the way a cell senses its environment through contact.Like hormones and cytokines, the sol- uble mediators used by cells for communication, adhesion molecules are defined molecular entities that recognize specific receptor structures on the surface to which they adhere. Recent activity has focused on defining the structure of the individual molecules responsible for many types ofcellularadhesion. New adhe- sion proteins are being cloned with the help of specific antibodies and precise functional assays.

The heat-shock proteins in E. coli are transiently overexpressed af- ter shift to a higher growth temperature. The genes that encode the HSPs are preceded by promoters transcribed in vitro by a form of RNA poly- 32 32 merase holoenzyme containing a 32-kd a subunit (Ea ). The a subunit is encoded by the rpoH (htpR) gene, previously identified as a positive 32 effector of the heat-shock response. Our evidence suggests that Ea is the enzyme that transcribes heat-shock genes at all temperatures. The level 32 of a may be regulated at several points: Accumulation of rpoH mRNA 32 is affected by temperature shift, a synthesis is regulated posttranscrip- 32 tionally, and a is an unstable molecule with a tl/2 of 5 min. Many mu- tations in the HSPs are shown to have defects in proteolysis. References Baker. T. A. , Grossman. A. D . . and Gross. C. A. , 1984, A gene regulating the heat shock response in Escherichia coli also affects proteolysis. Proc. Natl. A cad. Sci. US. A. 81:6779-6783. Bardwell, J. C. A . . and Craig, E. A . . 1984. Major heat shock gene of Drosophila and the Escherichia coli heat-inducible dnaK gene are homologous, Proc. Natl. Acad. Sci. US. A. 81:848-852. Bukhari. A. I. .and Zipser. D . . 1973, Mutants of Escherichia coli with a defect in the degradation of nonsense fragments, Nature New Bioi. 243:238-241. Charette. M. F. , Henderson, G. W. , and Markovitz, A.

It is less than 80 years since John Newport Langley first proposed the role of "receptive substances" as the site of drug action from his obser­ vations on the effects of nicotine and curare at the myoneural junction. The many advances in our understanding of receptor biology that have occurred during the intervening period mirror the extraordinary growth of knowledge in the biological sciences and in cell and molecular biology in particular. Receptor biology, in common with many other topics in contemporary biology, is on the threshold of a transition from being a descriptive, phenomenological discipline to one in which underlying mechanisms and regulatory principles can be defined with increasing pre­ cision. This change, together with the evolution of powerful analytical techniques and timely convergence of ideas from a number of previously separate fields of inquiry, is generating an increasingly unified theoretical and experimental framework for the study of receptor function. These themes, and the mood of anticipation that a real understanding of receptor function in health and disease is emerging, are reflected in in this volume, which summarizes the proceedings of the Sec­ the papers ond Smith Kline & French Research Symposium on New Horizons in Therapeutics held in Philadelphia in 1984.

This volume focuses on recent developments in our understanding of selected adhesion processes that may offer new approaches to developing therapeutics for a variety ofdiseases. The volume first introduces the molecules involved in key adhesive processes, then describes the biological consequences of several adhe- sive interactions, and closes with a description of the initial therapeutic ap- proaches to antagonizing. adhesion. These papers were originally presented at the SmithKline Beecham Pharmaceuticals Seventh U. S. Research Symposium held in Philadelphia in October of 1992. ofacell to asurface. In its simplestsense, cellularadhesion is the adherence The cells of interest in the context of this volume are bacterial and mammalian, with an emphasis on leukocytes; surfaces can be other cells and tissues (such as bone), matrix proteins, or inanimate objects such as in-dwelling medical devices and catheters. Interaction between adhesion molecules usually results in a spe- cific biological response. Adhesion is a form ofcellularcommunication, and represents the way a cell senses its environment through contact.Like hormones and cytokines, the sol- uble mediators used by cells for communication, adhesion molecules are defined molecular entities that recognize specific receptor structures on the surface to which they adhere. Recent activity has focused on defining the structure of the individual molecules responsible for many types ofcellularadhesion. New adhe- sion proteins are being cloned with the help of specific antibodies and precise functional assays.

The characterization of the cellular and molecular mechanisms that mediate inflammation provides a foundation that supports future studies that will de­ fine mechanisms more intimately. It encourages substantial optimism about the opportunities to understand the inflammatory process and to use that information to develop novel therapeutic approaches. Recent progress has defined the cells that mediate the inflammatory response, many of the inter­ cellular transmitters, the receptors, signal transduction processes and regula­ tory mechanisms. Thus, we now have the opportunity to understand inflammation in pharmacologic terms and to attack the key molecular targets to develop new therapeutics. Among the cells involved in the inflammatory response are the lympho­ cytes, neutrophils and endothelial cells. Maintenance of homeostasis, re­ sponse to proinflammatory stimuli and pathophysiologic responses are products of complex interactions between these and other elements of the immune systems. Each of these cells displays a variety of receptors to define the stimuli to which they respond. The receptors displayed that the signal transduction processes and cellular responses are regulated genetically and epigenetic ally . The critical role of membranes and particularly the phospho­ lipid components of the membranes is emphasized by recent studies.