FUNDING

Over the last 15 years, Dr. Kaddurah-Daouk has raised over $70 million dollars mainly through funding from the NIH while at Duke University that enabled her to lead four consortia that engage over 200 scientists across the globe. These consortia include 1) The Metabolomics Research Network, 2) Pharmacometabolomics Research Network, 3) Alzheimer's Disease Metabolomics Consortium, 4) Mood Disorder Precision Medicine Consortium, and 5) The Alzheimer Gut Microbiome Project. Funding related to Alzheimer's disease is detailed below.

METABOLIC AGE TO DEFINE INFLUENCES OF THE LIPIDOME ON BRAIN AGING IN AD

In this grant (1R01AG081322-01) we will use state-of-the-art lipidomics techniques to investigate how lipid metabolism and aging interactions impact immune and brain health and modify Alzheimer’s disease (AD) risk susceptibility.

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DATA INFRASTRUCTURE AND MOLECULAR ATLAS FOR AD: CONNECTION EXPOSOME, GUT MICROBIOME, AND METABOLOME

In this supplement to the Alzheimer Gut Microbiome Project (3U19AG063744-04S1), we propose to build research infrastructure that can expand coverage of the exposome including chemical exposures, food, drugs, and supplements where all data is made publicly available through the Sage Network. We will coordinate with other large exposome initiatives including Neighborhood Atlas (socioeconomic disadvantage), HHEAR and Netherlands Exposome Initiative (geolocation), biobanks and epidemiological studies (UK Biobank, FHS, Rotterdam) to start to create a Molecular Atlas for Exposome and its influences on AD.

CHARACTERIZING THE AD METABOLOME IN BRAIN TISSUES OF INDIVIDUALS FROM DIVERSE POPULATIONS

In this supplement to ‘Metabolomic Signatures for Disease Sub-Classification and Target Prioritization in AMP-AD’ (3U01AG061359-05S1) we propose to expand biochemical knowledge about metabolic failures in AD in minority participants harnessing the power of multiple cohorts with ethnically diverse samples by working with AMP-AD partners. By working with AMP-AD partners, we will systematically address contributions of racial differences on brain health by metabolomics and lipidomic profiling of brain samples collected as part of the AMP-AD initiative.

 

ALZHEIMER GUT MICROBIOME PROJECT

The Alzheimer's Gut Microbiome Project (1U19AG063744-01 ) seeks to define the role of the gut microbiome in AD pathogenesis and the biochemical axis of communication between the gut and the brain building upon large initiative and infrastructures co-established by our international multi-disciplinary team.

 

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METABOLOMIC SIGNATURES FOR DISEASE SUB-CLASSIFICATION AND TARGET PRIORITIZATION IN AMP-AD

Our ADMC is creating a comprehensive metabolomics database and an Atlas for the AD community that will provides a deep understanding of metabolic failures in AD and a roadmap for drug discovery (3U01AG061359-02S1). We will enable our AMP-AD partners with biochemical readouts that connect their findings to known biochemical pathways that can be targeted for drug discovery. We use metabotypes and genotypes to identify clinical subtypes to support a precision medicine approach to AD.

METABOLIC NETWORKS & PATHWAYS PREDICTIVE OF SEX DIFFERENCES IN AD & TREATMENT RESPONSE

In this grant (1RF1AG059093-01), we use global metabolomics approach to delineate biochemical differences in men and women across the trajectory of disease. We aim to define biochemical pathways and networks for greater vulnerability of disease in women and men that would enable discovery of more effective therapies for each sex.

 

GUT-LIVER-BRAIN BIOCHEMICAL AXIS IN AD

We seek to define gut bacterial composition and activity that mediate aberrant bile acid, lipid and amine profiles as well as other blood metabolites and their relationship to AD pathogenesis. Using cutting-edge computational systems biology techniques we seek to identify human and microbial genes, reactions, and pathways and their interplay that are involved in AD pathogenesis. We will evaluate the role of the gut-brain metabolic axis in the development of AD, with the ultimate goal of defining human and microbial genes and proteins that may serve as potential therapeutic targets (1RF1AG058942-01).

METABOLIC NETWORK ANALYSIS OF BIOCHEMICAL TRAJECTORIES IN AD

In this grant ( 1RF1AG057452-01 ), we enrich our effort in the ADMC by adding world experts in metabolic engineering to build an atlas for AD that captures global metabolic failures and their possible genetic basis. We propose to reconstruct the first genome-scale model of metabolic changes underlying AD progression. Together, this effort will provide a biochemical roadmap for novel drug discovery.

METABOLIC NETWORKS AND PATHWAYS IN AD

Our overall goal is to leverage large investments made by the NIH in the AD Neuroimaging Initiative (ADNI) and Pharmacometabolomics Research Network taking an integrated metabolomics-genetics-imaging systems approach to define network failures in AD (3R01AG046171)

METABOLIC SIGNATURES UNDERLYING VASCULAR RISK FACTORS FOR AD TYPE DEMENTIAS

We use state-of-the-art metabolomics/lipidomics and bioinformatics tools to define metabolic signatures and biochemical changes mechanistically related to vascular and metabolic conditions associated with AD risk. We leverage extensive biochemical and longitudinal clinical data generated by our ADMC using ADNI samples and those from a large community health study in NC, the 'MURDOCK Study'. (3RF1AG051550).

INTEGRATIVE TRANSLATIONAL DISCOVERY OF VASCULAR RISK FACTORS IN AGING AND DEMENTIA

In collaboration with the Mayo Clinic Jacksonville, we investigated the impact of ApoE genotype and sex on transcriptional networks and the serum and brain metabolome in AD model systems (RF1AG051504 ).

METABOLIC SIGNATURES FOR AD

We use complementary metabolomics technologies to capture comprehensive biochemical changes and biochemical signatures at various stages of AD in relation to pathologic and clinical status. We will perform CSF metabolomics in AD patients with pathologically confirmed diagnoses and matched controls to interrogate specific pathways. We will prospectively collect plasma samples and CSF samples from living AD patients and controls to test secondary hypotheses pertaining to utility of plasma metabolomics, and its correlation with CSF metabolomics as well as cognitive changes over time in the same set of individuals ( 3R01NS054008 ).

IU/JAX AD PRECISION MODELS CENTER: METABOLOMICS

The IU/JAX MODEL-AD Center is creating, characterizing, and testing the next generation of animal models for late-onset AD. To provide a deep understanding of the dysregulated processes involved in AD, we are performing detailed molecular and neuroimaging characterization on multiple mouse models (3U54AG054345).

AN INTERATED AMP-AD BIOMARKER DISCOVER STUDY

The goal of this supplement is to leverage the parent U01 AMP-AD grants, supplementing their emerging AD network maps with selected fluid-based metabolomic data to enable biomarker discovery. Identification of peripheral blood and CSF features that relate to the brain molecular networks will facilitate the translation of novel targets and biomarkers emerging from AMP-AD: it will allow better trial designs in optimal subsets of the subject populations once lead compounds against AMP-AD targets emerge.

METABOLIC SIGNATURES IN THE ROSMAP COHORT

This supplement extends the metabolomic profiling under the parent grant (R01AG046171), to include participants for which there are multiple layers of brain omics data already available including genomic, epigenomic, RNAseq, and proteomic.

TARGET AD: SYSTEMS MULTI-OMICS APPROACH TO DRUG REPOSITIONING IN AD

This subaward (1R01AG069902) is part of the Accelerating Medicines Partnership - AD (AMP-AD). The overall goal is identify drug repositioning candidates in a network-based framework by combining multi-omics associations from large studies of AD with molecular pathway information, extensive drug-drug target data, as well as molecular drug effect data