- OVERALL Both human bone and heart present remarkable anatomical, cellular and functional heterogeneity, with specialized cellular structures performing distinct yet essential physiological functions. A significant gap of knowledge is that different cells' molecular signature, spatial distribution and interactions, and functional state remain little understood for both organs. Although spatially separated, growing evidence suggests that a bone- heart communication axis plays a critical role in normal development and pathogenesis of these two organs and possibly other organs. Joint analysis of the two organs could reveal novel insights into the microenvironment organization and signaling pathways underlying the inter-organ communication. We therefore propose the in-depth characterization of these two organs which, together, account for a large fraction of human disease burden. We will map molecular and cellular changes in the tissue over the course of human lifespan using comprehensive multi-dimensional single-cell and imaging technologies. The final product will impact research of these two organs in the following manner: 1) Organ Atlases: spatially resolved atlases will provide a highly user friendly, publicly available, searchable database of the most comprehensive multi- omic, single cell analysis of the two organs. Molecular data will be richly annotated with additional clinical and epidemiological data. 2) Computational methods: in addition to the data, the critical computational tools and pipelines developed in this project will be available to the research community. These include methods and pipelines for processing multi-omics and imaging data, inference of cell-specific regulatory and signaling pathways, correlation of mesoscale imaging and molecular imaging features, as well as database algorithms for the query, exploration and visualization of highly complex data. 3) Access to biospecimens for follow-up studies: biospecimens collected in this project will be banked and made available to the biomedical research community. These include freshly frozen and fixed specimens and tissue sections. In summary, the proposed project will broadly impact the entire research community and jumpstart basic-science and medical discoveries based on a sophisticated understanding of the key molecular circuits underlying the development and aging of these two organs.
Bone and heart are vital organs for human health. Our in-depth characterization of these two organs will lead to improved understanding of blood, bone and heart diseases and have the potential to greatly change the outcomes landscape of these diseases.