Pneumocystis pneumonia (PCP) is a fungal disease associated with immunosuppressive conditions such as AIDS, cancer, rheumatic disease, organ transplant, malnutrition, etc. The biology of this fungus is poorly understood, research tools are limited and current treatments are inadequate. We demonstrated that Pneumocystis depends on its host for the critical biochemical intermediate S-adenosylmethionine (AdoMet), that PCP causes a reduction in host lung and plasma AdoMet, that systemic nicotine treatment to reduce lung AdoMet decreases vulnerability to PCP in an animal model, and that AdoMet infusion increases the intensity of animal model PCP. Our goal is to develop a new approach to PCP prophylaxis & treatment: limit the availability of AdoMet necessary for Pneumocystis growth.
The first Aim i s to resolve the biochemistry of lung-specific AdoMet depletion induced by systemic nicotine infusion; this information will help identify molecular targets for drug discovery research. We know nicotine induces polyamine catabolism in lungs, but we don't understand the differences in responses of other organs. We will compare biochemical responses of lung, liver and kidney of animals infused with nicotine by analyzing tissue explants prepared from nicotine-treated and control animals using a combination of metabolic flux and enzyme assay methods. We know that only some lung cells respond to nicotine with AdoMet reduction and our second Aim is to determine which cells respond; this information is needed to understand the response, to identify the nicotine target, and to develop an in vitro model needed for further drug development. We will isolate lung cell types for biochemical & proteomic analyses and examine lung sections for differences in metabolic enzyme expression.
Our third aim i s to determine the best metabolic targets for altering the supply of AdoMet for Pneumocystis: targets to decrease the supply thereby treating/preventing PCP. We will also determine the relative importance to Pneumocystis of AdoMet obtained from lungs and from the entire extracellular pool.
Pneumocystis pneumonia (PCP) affects many people with weakened immune systems, but the biology of this fungal disease is poorly understood and current treatments are inadequate. We discovered that Pneumocystis depends on a nutrient from lungs (S- adenosylmethionine) and that by reducing it with nicotine treatment we suppress PCP in an animal model. We aim to develop this new treatment lead by determining why whole body nicotine treatment reduces this nutrient only in lungs, which lung cells are responsible for the reduction, and whether the same effect can be achieved with treatments other than nicotine.
| Liu, Chunli; Perez-Leal, Oscar; Barrero, Carlos et al. (2014) Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis. Amino Acids 46:701-15 |
