SINGLE-CELL RESOLUTION ANALYSES TO IDENTIFY CELL-SPECIFIC ESTROGEN SIGNALING PATHWAYS IN BONE

Fractures caused by bone loss are associated with suffering and increased mortality in patients and great costs for society. Estrogen protects the skeleton and prevents bone loss. However, the use of this hormone as a therapeutic drug against bone loss is restricted due to adverse effects.

Estrogen signaling is regulated in a cell-specific manner, and I hypothesize that identifying cell-specific estrogen signaling pathways, using state-of-the-art transcriptome profiling techniques and novel transgenic mouse models, will result in bone-protective therapeutic agents with less adverse effects.In this five-year proposal, I will use single-cell RNA sequencing and spatial transcriptomics to determine the cellular and molecular mechanisms behind estrogenic effects in bone.

In addition, my pivotal findings that membrane-initiated estrogen receptor alpha (mERα) signaling, and estrogen signaling in neuronal cells, affect bone mass, will be followed up, and the mechanisms behind mERα- and neuronal ERα-mediated effects on the skeleton will be determined using novel transgenic mouse models and a chemogenetic approach.Overall, this project will determine the effects of estrogen on the transcriptome profile in bone at single-cell resolution and identify the mechanisms behind mERα and neuronal ERα signaling effects in bone, thereby aiding the development of new cell-specific treatments against bone loss.