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Mitochondrial Function and Multiomics in Aging-related Disease: Identifying Novel Biomarkers and Causal Relationships

US · IL NIH grant awarded #nih-5R01AG085753-03

Summary

This project aims to identify novel biomarkers and causal relationships between mitochondrial function and aging-related diseases, such as all-cause mortality, cardiovascular disease (CVD), and frailty, by integrating multiomics data from large biobanks.

What they want

The project will comprehensively assess mitochondrial function, including mtDNA copy number, homoplasmy, and heteroplasmy, in 680,000 subjects, combined with plasma metabolomics and proteomics. It will identify plasma metabolites/proteins associated with mitochondrial function using Mendelian randomization (MR) in UK Biobank (UKB) and TOPMed samples. Phenotypic associations between mitochondrial function biomarkers and aging-related diseases will be established and validated. Causal relationships will be discriminated using MR, involving GWAS of nuclear variants and causal mediation analysis. Finally, systems biology approaches will identify relevant genes and functional variants for experimental validation, characterizing mitochondrial function and quantity.
Deliverables
  • Identification of novel causal associations between mitochondrial function and all-cause mortality, CVD, and frailty
  • Identification of plasma metabolites/proteins associated with mitochondrial function
  • Identification of orthogonal biomarkers of mitochondrial function
  • Established phenotypic associations between mitochondrial function biomarkers and aging-related diseases
  • Discrimination of causal from non-causal associations of mitochondrial function biomarkers and aging-related disease
  • Identification of instrument variables for Mendelian randomization
  • Identification of relevant gene(s) at each locus and mapping of putative functional variants
  • Characterization of identified genes by assessing mitochondrial function (e.g., cellular respiration, glycolytic flux) and quantity (nucleoid density, mass)
  • Identification of readily measurable biomarkers of mitochondrial function
  • Identification of causal genes and therapeutic targets for aging-related diseases
Technical requirements
  • Whole-genome sequence (WGS) data analysis
  • Plasma metabolomics
  • Proteomics
  • Mitochondrial DNA copy number (mtDNA-CN) measurement
  • Assessment of mtDNA homoplasmy and heteroplasmy
  • Mendelian randomization (MR) analysis
  • Genome-Wide Association Studies (GWAS)
  • Causal mediation analysis
  • Systems biology approaches
  • Experimental validation (e.g., cellular respiration, glycolytic flux, nucleoid density, mass assessment)

Market context

inferred from NAICS
Professional, Scientific & Technical Services
NAICS 541714
US market size
$2.0T
Typical award
$25K – $50M
Typical buyers
All federal civilianDoDStates
Commonly required
8(a)WOSBSDVOSBPE/PMP

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