COBRE in Mesenchymal and Neural Regulation of Metabolic Networks

COBRE PROJECTS

Project 3:  A pharmacogenomic study of beta adrenergic receptor signaling on bone and metabolic phenotypes. –  Dr. Christine Lary

Motivation

  • Bone fragility contributes to significant morbidity and mortality, increased medical costs, and reduced quality of life
  • Beta Blockers improve bone metabolism and offer therapeutic benefit to patients at high risk of fracture
  • Estimates of Beta Blocker effect have varied potentially due to heterogeneity in type of drug
  • Mechanism of Beta Blocker response has been studied in mice (Figure 1) but it is not well characterized in humans

Figure 1: Putative mechanism of bone response to Beta Blocker use. Adapted from Elefteriou, F. “Neuronal Signaling and the Regulation of Bone Remodeling.” Cellular and Molecular Life Sciences CMLS, vol. 62, no. 19, Oct. 2005, pp. 2339–49.

 Hypothesis

  • Bone outcomes are modulated through Sympathetic Nervous System (SNS)-mediated mechanisms that can be perturbed via Beta Blocker use depending on genetic variants in the beta adrenergic receptors.

 Proposed Study

  • Use the Framingham Osteoporosis Study to examine the association between Beta Blocker use and bone phenotypes including:

∗Hip and spine bone mineral density
∗Bone microarchitecture and strength with high-resolution peripheral quantitative computed tomography (HR-pQCT)
∗Risk of osteoporotic fracture

  • Examine the association between ADRB1 and ADRB2 genetic variants and bone phenotypes
  • Discover molecular correlates of bone phenotype variation according to Beta Blocker use using multi-omic data integration

∗Analyze microRNA and mRNA gene expression data from whole blood

 Anticipated Results

  • Characterization of the effect of Beta Blocker use on bone phenotypes
  • Description of genetic variation underlying Beta Blocker effect on bone phenotypes
  • Hypothesized mechanisms and putative biomarkers of Beta Blocker effect for validation in future studies

Team

The study team consists of investigators at five institutions with a wide range of expertise. The disciplines covered include biostatistics, bioinformatics, genetics, pharmacopepidemiology, molecular biology, pharmacology, gerontology, and genetic epidemiology (see Figure 2).

Figure 2: Study Team