Developing Biomedical Projects Portfolio

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PROJECT SUMMARY – DRIVING BIOLOGICAL PROBLEMS Inorganic chemistry plays myriad, evolutionarily-conserved roles in physiology and pathology. Cells must accumulate several metals, such as zinc and iron, to millimolar levels in order to survive. They can deploy fluctuations in metal content to control processes as varied as the mammalian cell cycle, pathogen infection and neurological function. The critical regulatory role of metals is emphasized by the observation that one- third of all protein-encoding genes in the human genome encode metal-dependent proteins. There is an increasing appreciation in the NIH research community that intracellular content and subcellular location of each element provides an inorganic signature that serves as a quantitative phenotype. These realizations are driving the demand for new technologies for quantitative evaluation of inorganic signatures in cells and tissues. Such methods are essential to understanding the regulation of physiological and pathogenic processes and developmental decisions. The proposed Resource will address two grand challenges. The first is to understand how metals act within single cells to affect cell function. The second is a matter of scale: how can we efficiently analyze millions of samples to search for correlative markers of health and disease in the human population? The proposed Resource for Elemental Imaging for Life Sciences (QE-Map) will develop and integrate emerging technologies to create transformative approaches to the compelling biological question concerning inorganic chemistry in health and disease. Neither of these challenges can be addressed with current technology. The technologies to be developed comprise a suite of three imaging and detection methods that will allow investigators to quantitatively map the distribution of dozens of elements in samples ranging from cell extracts to fixed cells to tissue slices. A portfolio of twelve DBPs was selected for their capacity to enable iterative development of new methods, and address high impact research questions in the field of “inorganic physiology.” The DBPs focus on four themes: (a) metal regulation in brain function and pathology; (b) metal modulation of host-pathogen interactions; (c) metal fluxes controlling reproduction and development; and (d) metal imbalances in metabolic pathology. The External Advisory Committee will oversee the turnover of DBP projects to maintain a portfolio is broad in scope and responsive to the needs of the national research community while advancing and stimulating QE-Map technology development. The DBP Program Leader, Tom O’Halloran, will deploy multiple strategies establish and strengthen collaborative relationships between the DBP investigators and the technology development teams; including kick-off meetings, collaboration apps, and all-Resource meetings.