Unlocking the key to strong bones: functionally… (F32AR085941) – Project Grant to Rector & Visitors Of The…

Abstract: Osteoporosis is a complex, age-related disease characterized by decreased bone mineral density (BMD), deterioration of bone microstructure, and an increased risk of fractures. IT is a major public health concern associated with significantly increased morbidity and mortality. Family history is among the strongest risk factors for osteoporosis and related traits. Genome-wide association studies (gwass) have identified over 1,000 independent associations with BMD. However, most of these variants reside outside gene-coding regions, making IT challenging to pinpoint the affected genes. Transcriptomic data offer a powerful means to bridge this GAP by providing insights into gene expression and regulatory mechanisms, yet such data remain scarce for human bone tissue. To address this, we will generate the first population-scale transcriptomic dataset derived from bone tissue collected from patients undergoing HIP surgery. In aim 1, we will integrate these data with genotypic information to identify genetic variants that influence gene expression in bone (expression quantitative trait loci, eqtl). By mapping these regulatory variants to BMD-associated loci, we will determine how they may influence BMD through changes in gene expression. Since bone, like all tissues, comprises multiple cell types, we will also generate single-cell RNA-SEQ data from a subset of samples. An integrative analysis of single-cell and bulk RNA-SEQ data will provide cell-type-specific context for BMD- associated eqtl, offering deeper insights into the regulatory mechanisms underlying osteoporosis. In aim 2, we will further investigate the functional consequences of these findings by using crispr interference (crispri) in human fetal osteoblasts (hfobs) to selectively repress 20 effector gene candidates identified through eqtl analysis. We will assess the effects of gene repression on key osteoblast functions, including proliferation, migration, and mineralization. As the cells responsible for bone formation, osteoblasts offer a highly relevant system for investigating how genetic regulation influences skeletal maintenance. These functional assays will not only elucidate the molecular mechanisms affecting bone health but also advance the identification of potential therapeutic targets for osteoporosis. The training plan outlined in this application is designed to prepare the candidate for an independent research career in multi-omics of age-related diseases. The candidate will utilize the expertise of the sponsor's lab to become proficient in genetics and gain wet lab experience that will complement her previous training in computational epigenetics and strengthen her capacity to integrate experimental and computational approaches. She will develop a strong understanding of bone biology and the molecular biology of age-related changes to bone health. The department of genome sciences at the university of virginia, which focuses on genome studies of human health, provides an excellent environment for such training. The training plan further outlines a strategy to enhance the candidate's leadership skills essential for establishing a successful independent research lab.

Unlocking the key to strong bones: functionally defining the role of genetic drivers in osteoporosis

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