Multifaceted molecular MRI toolbox to uncover Zn2+ in physiology and pathology

ongoing

To reveal the multiple aspects (molecular, cellular and anatomical) of a studied biological process (in health or disease), it is necessary to have the ability to spatially map the multiplexity and dynamicity of intra- and inter-cellular events in the context of a whole organism. We here propose a conceptually novel approach to spatially map the multicomponent information of a studied biological phenomenon, from the deep tissue of a studied subject using a single imaging setup. In realizing the importance and diverse roles of labile Zn2+ in specific tissues, we aim to develop ZincMRI. ZincMRI is a molecular imaging toolbox designed to provide orthogonal MRI readouts, with which we aim to monitor the multiple facets of Zn2+ biology through: (i) quantitatively mapping dynamic changes in intra- and extra-cellular levels of Zn2+; (ii) spatially monitoring Zn2+-induced gene expression, and (iii) providing complementary high-resolution anatomical views of the studied subject. To establish ZincMRI, we will design, develop, and implement: (i) fluorinated synthetic compounds as MRI responsive agents for quantitatively mapping changes in labile Zn2+ levels using 19F-MRI (Aim 1); and (ii) conditional MRI reporter genes for mapping Zn2+-induced transcription with 1H-CEST MRI (Aim 2). Capitalizing on the orthogonality of the signals obtained with 19F-MRI and 1H-CEST MRI, ZincMRI will be applied to map, in vivo, from the hippocampus region of the brain, both the dynamic changes in Zn2+ levels and the transcription of Zn2+ regulatory elements in response to physiological and pathological stimuli (Aim 3). We envision that ZincMRI, which unconventionally aims to study two aspects of Zn2+ biology using a single imaging modality, and is also applicable for the study of deep tissues, may affect not only the way we study this ion, but could also be further extended to study other metal ions with biological relevance by capitalizing on the scientific paradigm proposed here.