Project Summary – Bioinformatics Core The objective of this Bioinformatics Core is to support statistical and bioinformatics analyses to study the effects of osteoporosis anabolic therapies (romosozumab, a sclerostin inhibitor, Scl- Ab) on osteoblast progenitors as well as osteocytes in clinical and pre-clinical studies with anabolic therapies. A short anabolic treatment window from Scl-Ab has been reported; in contrast to teriparatide (PTH) that has a longer anabolic window. This Bioinformatics Core will serve as the critical foundation for the research projects by analyzing cross-species data from single cell RNA-seq (scRNA-seq) and bulk RNA-seq using innovative techniques and approaches. The capabilities of the Bioinformatics Core will be enhanced by being able to leverage existing datasets of whole genome sequencing in tens thousands of human samples; and osteocyte gene expression signatures and deeply skeletal phenotyping from a unique mouse knockout dataset from our collaborators. To support Project #1, Project #2 as well as pilot projects, the Bioinformatics Core will provide statistical design, computational analysis, data quality control and management support as well as accessing to other external human genetics and bioinformatics data and resource. Specifically, in Aim 1, the Bioinformatics Core seeks to build a synergistic data management, data analytical and bioinformatics pipelines over cloud computing environment which allows interaction within investigators through data collection, data analyses, information sharing and data interpretation. In Aim 2, the Core will provide statistical and bioinformatics analyses for scRNA-seq and bulk RNA-seq generated from clinical and pre-clinical studies to identify osteoblast precursor cell clusters over time with either Scl-Ab or PTH treatments; osteoblast lineage tracing; osteoblast progenitors and osteocytes gene expression patterns; and co-expression pattern over time. In addition, cross-species integrating analysis will be conducted to identify homologous and divergent cell types between human and mice. In Aim 3, we will prioritize genes regulating bone formation and Identify molecular signatures affecting treatment effect via human gene expression (in bone biopsies) and genetic variation associated with bone phenotypes (BMD, HR-PQCT derived bone structure, fracture) in large-scale whole genome sequenced studies. In Aim 4, To further characterize skeletal function and phenotypes of the genes identified from project# and project#2 transcriptome analyses, we will utilize the existing KO mice deep phenotyping data; and generate a new KO mice strain. Ultimately, these merged analyses will generate powerfully informed, novel hypotheses regarding bone stem cell biology and responses to bone anabolic agents.