The goals of this project are (i) to understand how cells manage and utilize heme, an essential but toxic nutrient, and (ii) to educate, train, and diversify a new generation of scientists. Heme is required by much of life, enabling a vast number of proteins and cellular processes to function properly. However, heme is also known to promote cellular dysfunction due to its toxic properties. How do cells and organisms utilize heme while mitigating its toxicity? The PI proposes that there are distinct molecules that help shuttle heme to different locations in a controlled manner and various physiological stimuli can initiate heme mobilization. Using heme sensors recently developed in the PI's laboratory, graduate, undergraduate, and high school/middle school students will collaborate to determine how cellular heme is handled and mobilized throughout the cell. This research will not only reveal the manner by which cells manage an "essential toxin" like heme, but also provide new tools and methodologies that will benefit the large community of scientists that study heme. Moreover, the research will be used as a vehicle to promote participation of under-represented minorities in science. A long-term scientific mentorship program will be developed in which Hispanic middle school students from metro-Atlanta will work with the PI's group to implement the research.
Heme is well known as an essential iron containing cofactor. A number of heme regulated factors and processes are conserved from yeast to man, suggesting a role for heme as a dynamic signaling molecule. This project aims to reimagine and expand the role of heme in cell biology as a signaling molecule. The cytotoxicity and hydrophobicity of heme requires that it be trafficked in a highly coordinated manner from its site of synthesis in the mitochondria to hemoproteins present in every subcellular compartment, including the nucleus. However, the molecules and mechanisms that mediate the initiation, transmission, and integration of heme-based signals and the spatio-temporal dynamics of heme mobilization for trafficking and signaling are unknown. This is in large part due to the lack of tools available to image labile heme pools relevant to trafficking and signaling. The PI's group has recently overcome this major technological barrier by generating genetically encoded ratiometric fluorescent heme sensors. The project will utilize these heme sensors in conjunction with mass spectrometry based proteomics and yeast molecular genetics to delineate the molecules and mechanisms that mediate heme trafficking and signaling and their dynamics.
