It is proposed to continue biochemical studies of parasitic helminths which have been inaugurated over the previous 20 years of this proposal (AI-09483). Particular emphasis will continue to be placed on the intestinal roundworm, Ascaris suum, the filariids, Brugia pahangi, Litomosoides carinii and Dipetalonema viteae, the cestode Hymenolepis diminuta and the trematode Fasciola hepatica. A number of striking differences have been shown to exist at the level of overall metabolic pathways, including energy yielding reactions, as well as at the more subtle levels of enzyme kinetics, regulation, structure and intracellular distribution of enzymes. Such differences are vulnerable to chemotherapeutic attack. Detailed metabolic studies of the parasitic helminths will continue in an effort to attain a more precise appreciation of the comparative aspects of host and parasite biochemistry which, in turn, is essential for a more basic understanding of host-parasite and parasite-drug interactions. Specific areas of investigation will include: a) The mechanism and tightly coupled regulation of succinate and volatile fatty acid formation by adult Ascaris. b) Comparative studies of energy generating reactions in the mitochondria of Ascaris and other helminths. These are quite different from the corresponding reactions of mammalian systems, and include substrate level phosphorylation from the decarboxylation of succinate to propionate, as well as electron transport associated generation of ATP. c) The metabolism of the Ascaris reproductive system, which differs considerably from that of the nematode muscle, will be examined. d) Relationships between membrane lecithins, glycerophosphorylcholine and signal transduction will be probed. e) Studies of energy and oxidation will be inaugurated to examine the function of highly cristaeted mitochondria in the apparently homolactate fermenting filariid parasites. f) Additional vulnerable sites for anthelmintic activity and the modes of action of anthelmintics upon metabolic reactions in the parasite will be considered. g) New techniques of electrophysiology and neuropharmacology of D. viteae have been developed and will be used employing microelectrodes placed in individual somatic muscle cells. h) The non-invasive technique of 31P and 13C Nuclear Magnetic Resonance will continue to be employed to examine metabolism and drug action in intact Ascaris and Fasciola hepatica.
