The fundamental functions of biological membranes are to serve as general permeation barriers and at the same time allow the selective permeation of certain types of molecules. The structural basis of these functions will be studied at the molecular level by using three different membrane systems. (1) The outer membrane, located outside the cytoplasmic membrane and peptidoglycan layer of Gram-negative bacteria, is an ideal model membrane for the study of this type, because its functions are very simple in that it allows only passive and facilitated diffusion processes. The diffusion of hydrophilic molecules is mediated by porin and other channels, and it is proposed to characterize the properties of these channels in detail. Furthermore, the lipid domains of the outer membrane show an unusually high resistance tothe diffusion of hydrophobic molecules. By studying the molecular basis of this resistance by the use of mutants, agents that increase the permeability of this domain, and various biophysical techniques, we hope to gain insight on the molecular basis of the barrier property of this unusual lipid bilayer. The results of these two lines of work will be of potential medical significance, because the most effective weapon of many gram-negative opportunistic pathogens that are currently causing problems in hospital-related infections is the generalized antibiotic resistance caused by the low permeability of the outer membrane. Thus the outcome of this study will be able to provide methods for increasing the permeability of chemotherapeutic agents through the outer membrane, either via the modification of their structures so that they can pass through the porin channel more rapidly, or by interfering with the organization of the lipid domains so that their permeability to all agents are increased. (2) The molecular mechanism of active transport of maltose will be studied by characterizing the protein components and eventually by attempting reconstitution. """"""""Binding-protein-dependent"""""""" transport systems such as this one are not understood at all in terms of their mode of action, and this study is hoped to serve as a model for many such systems that operate in various Gram-negative bacteria. (3) Finally, the properties of the gap junction channel, which connects the cytoplasms of the neighboring animal cells, will be studied by reconstitution approach. This study has implications in the study of cellular differentiation and of the process of development of tumors, as the disappearance of gap junction channel is one of the earliest events in the development of solid tumor.
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