Copper is an essential nutrient. It is required for several critical functions such as iron transport, ATP synthesis, pigmentation, formation of connective tissue and neurotransmission. Menkes disease is a lethal disorder of copper deficiency. The protein defective in Menkes disease is the MNK copper transporting P- type ATPase. It is located in the trans-Golgi network where it transport copper into secretory compartments to copper-dependent enzymes. When copper concentrations are elevated, the MNK protein traffics to post- Golgi vesicles and the plasma membrane where it exports copper from the cytoplasm. The past decade has witnessed the identification of most, if not all, of the proteins that regulate intracellular copper homeostasis. However, despite these achievements, we still have little understanding of how copper is made available for adaptive responses to certain conditions. For example, copper is critical for new blood vessel growth, a process that is normally inactive but stimulated in response to oxygen depletion or inflammation. It is clear that copper has transient roles during certain conditions or pathologies, however, we have little understanding of the adaptive responses that may regulate copper pathways to meet these needs. Our preliminary studies demonstrate that the MNK protein in macrophages responds to inflammatory agents and oxygen depletion by the trafficking and increased expression of the MNK from the Golgi. We hypothesize that these responses regulate anti-microbial and angiogenic function of macrophages. Such processes are likely to impact a variety of inflammatory diseases such as Alzheimer's disease, cardiovascular disease and cancer. It is the goal of this proposal to understand and characterize the role of the MNK protein in macrophage function. To achieve these goals, we propose the following specific aims- SPECIFIC AIM 1: To investigate the mechanisms of copper homeostasis in macrophages during inflammation and oxygen limitation.
SPECIFIC AIM 2 : To investigate the role of Menkes protein in the anti-microbial activity of macrophages.
SPECIFIC AIM 3 : To investigate the role of the Menkes protein in the biology of macrophage- mediated angiogenic responses
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