The goal of this proposed project is to understand the effects of the microbiome on skeletal health in humans. We will determine if the microbiome plays a modulatory role on BMD, microarchitecture and strength in men and women from two population-based cohorts, the Framingham Study Third Generation (Gen3) and the Osteoporotic Fractures in Men (MrOS) cohorts.
The purpose of this proposal is to create a valid and practical prediction tool that will discriminate long-stay nursing home residents likely to reduce their fracture risk by taking an effective medication, and to identify which osteoporosis medications prevent fractures in long-stay residents.
After performing high resolution peripheral quantitative computed tomography scans on close to 2,000 Framingham Study participants, the microarchitectural indices obtained from the images will be used to perform genome wide association studies, to study risk factors for bone microarchitecture, and to determine if bone microarchitecture predicts fracture.
The overall goals of this project are to 1) create a database cataloguing and harmonizing the available data (diagnoses, phenotypes, epigenomic/genomic data, and covariates) and resources (stored biological samples) across participating studies, 2) pilot approaches using different epigenetic mechanisms, tissue samples, and statistical methods to study the role of epigenetics in the relationship between aging and disease, and 3) set up an infrastructure to aid planning of the overall project, including biweekly meetings, semi-annual one-day scientific workshops, and a steering committee to oversee the development of the final study design.
Disability This project will develop and evaluate diagnostic cut-points for low muscle mass and muscle strength that predict an increased risk of mobility disability among older adults, defined operationally as usual gait speed < 0.8 meters/ sec. The project is analyzing pooled data from two types of studies that include large number of individuals with mobility disability to accomplish the aims listed below: 1. Studies of community-dwelling older adults, limited to participants with mobility complaints; 2. Carefully characterized clinical populations of patients with heart failure, hip fracture, knee osteoarthritis (knee OA), or human immune-deficiency virus (HIV)-infection at risk for mobility disability, and randomized trials of older adults with low muscle mass, low muscle strength or mobility limitation.
This project is rooted in the evaluation and identification of likely causal chains of molecular and physiological activity connecting genetic variants to key aspects of human longevity for which pharmacological intervention at points in these chains could impact longevity. Our approach begins with longevity associated variants (LAVs) which we will identify and prioritize from published genome wide association study meta-analyses of longevity and from multivariate analysis of results from GWAS of longevity-related phenotypes to identify variants with pleiotropic effects. Potential LAVs will also be identified from genetic associations with human phenotypes that are likely to be influenced by genetic networks known to modulate aging in model organisms. Computational tools and curated resources of genomic functional characterization will be used to perform functional annotation of LAVs to identify the likely immediate functional impact of associated variants, such as the disruption of protein structure or a transcription factor binding site. We will employ methods that leverage tissue-specific genomic functional annotation to aid in the identification of tissues that might be relevant for genetic associations with longevity. We will assemble data and provide tools to determine if a variant may impact gene products/molecular phenotypes such as RNA expression that could be pharmacologically manipulated. Recognizing that genes do not work in isolation, but rather as part of networks or pathways with likely feedback and redundancy mechanisms, we will provide resources for assessing the role of a gene impacted by a LAV in the context of the functioning of gene networks or pathways. For this, we will use methods for assessing the ‘importance’ of a gene in network functioning and network information flow based on the topology of the network. Such analyses can lead to insights into how the manipulation of a gene may impact more downstream processes relevant to the development of a druggable target for longevity.
Predicting Hip Fracture using a Biomechanical Approach
NIAMS R01 AR060816
The specific goal of this study is to investigate the contribution of trochanteric soft tissue thickness to hip fracture risk, and to include this in the biomechanical Factor-of-Risk model. We hypothesize these factors predict hip fracture, and further that the factor-of-risk prediction of hip fracture risk will prove better than BMD assessment alone and better than the World Health Organization FRAX tool.
Risk Factors for Age Related Bone Loss
NIAMS R01 AR41398
This is the fifth 5-year continuation of this project examining both genetic and lifestyle factors influencing age-related bone loss and fractures. The project involves the performance of a high resolution peripheral quantitative computed tomography scans on 3,500 Framingham Study Third Generation participants and the analysis of computed tomography scans of the paraspinal musculature to study the contribution of visceral adipose tissue to bone and muscle status
This is a multicenter randomized placebo controlled trial of exercise with and without testosterone in women who have recently sustained a hip fracture and have completed their traditional rehabilitation. HSL is one of six clinical sites nationwide who will recruit women to participate in this study to improve mobility during recovery from hip fracture
To overcome these challenges and get better understanding of genome wide association study findings, we proposed to utilize whole genome sequencing in large well-phenotyped populations as well as the CRISPR/Cas9 gene-editing zebrafish model to identify potential causal variants and targeted genes influencing skeletal integrity. Findings from this work may eventually lead to new diagnostics and therapeutics of osteoporosis.