Decoding the regulatory impact of non-coding variation on MSC lineage commitment and osteoporosis risk

Active Project Grant Awarded Last action

Award ID
F30AG104788
Recipient
Awarding agency
Obligated
$55,114

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Place of performance
Bronx, NY 10461, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Osteoporosis is an age-related disease marked by declining bone mineral density and increased fracture risk. Although genome-wide association studies have identified hundreds of loci associated with bone traits, the biological mechanisms linking these associations to impaired osteoblast formation remains poorly understood. Over 90% of risk-associated variants LIE in non-coding regions, highlighting their potential roles in disrupting transcriptional regulation of lineage specific genes during osteogenic differentiation of mesenchymal stem cells (MSC) contributing to age-related bone loss. This project investigates how functional non-coding variants (FNCVS) in early osteogenic CIS-regulatory elements alter transcription factor binding, biasing mscs towards adipogenesis. Using both molecular assays and insights from large-scale population studies gives a unique opportunity to provide mechanistic insight into the biological mechanisms underlying age-related bone loss and osteoporosis, revealing new molecular targets for therapeutic intervention. Using a deep-learning model chrombpnet trained on an MSC atac-SEQ time course dataset generated in the greally lab, several candidate FNCVS predicted to alter regulatory programs governing osteoblast commitment were identified, including variants predicted to disrupt AP-1 binding at enhancers of WNT7B and other osteoblast regulatory genes. Aim 1 will include fine-mapping and functional validation of prioritized FNCVS using crispr editing, lineage assays, and allele-specific chromatin and transcriptional assays to define the regulatory mechanisms disrupted by risk alleles. Aim 2 will evaluate the contribution of validated variants to osteoporosis across global ancestry groups using biobank-scale data from the all of US research program to identify joint and interaction effects that shape clinical risk. Aim 3 will test whether early metabolic interventions targeting MTORC1 signaling can rescue defective WNT7B metabolic programming and osteogenic differentiation in fncv-edited mscs, providing proof- of-concept that regulatory variants can reveal actionable therapeutic pathways. This fellowship will provide integrated training in functional genomics, genome editing, and population genetics within the multidisciplinary environment of DRS. John greally and srilakshmi RAJ at albert einstein. Additionally, this work will be accompanied by relevant professional development, coursework, and clinical training activities to support development towards a future career as a physician-scientist. The rich scientific environment informed by a strong commitment to clinically informed research at montefiore einstein offers an excellent training environment to implement a study of age-related osteoporosis that bridges basic science, bioinformatics, and clinical applications. The mechanistic validation and therapeutic rescue experiments informed by population- level genomic data will establish a generalizable framework for translating non-coding variant biology into precision strategies for preventing and treating age-related conditions like osteoporosis.

Quick answers

Who received award F30AG104788?

F30AG104788 was awarded to Albert Einstein College Of Medicine by National Institute on Aging (National Institutes of Health) on February 25, 2027.

How much is award F30AG104788 worth?

$55,114 has been obligated on F30AG104788.

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