Grants and Contracts Details
Description
Management of inflammatory bowel disease (IBD) patients requires knowledge of disease status to inform
treatment decisions. Commonly used biomarkers such as clinical disease activity indices, C reactive protein
(CRP) and fecal calprotectin achieve suboptimal sensitivity and specificity for intestinal inflammation1. Data
provided indicate that peripheral blood exosome (PBE) lipid composition distinguishes active IBD from
normal patients (Fig. 1). We contend that PBE lipid compositions will provide clinicians with a highly sensitive
and specific biomarker to assess disease activity without invasive testing. The need to identify subtle disease
derives from the consensus conclusion that “deep remission” should be the endpoint of therapy. Thus,
monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment
goal2. Exosomes are lipid-encased, subcellular (60-80 nm) structures released into the peripheral blood at from
intestinal epithelial cells (IEC), activated leukocytes (e.g. neutrophils, macrophages, dendritic cells, etc.) and
mesenchymal cells during inflammation3. We used an ultrahigh resolution Orbitrap mass spectrometer to analyze
lipid compositions of PBEs from patients (>25/group). Principal component analysis (PCA) of PBE lipid intensities
showed a wide separation of datapoints between active IBD and normal controls and a heatmap analysis of
differential abundance revealed high within-group correlations and low between-group correlations suggesting
that distinct lipids can be resolved that correlate with disease activity. In this two year project, we propose to
collect plasma from 1) moderate-severe, 2) mildly-active and 3) quiescent Crohn’s disease (CD) patients as well
as 4) normal and 5) inflammatory (Clostridia difficile-infected) controls. Using CD allows us to test whether PBE
composition detects levels of mild (in many cases, subclinical) disease activity as this identifies patients not in
deep remission, a goal of medical therapy ( ). In Aim 1, PBE lipid-based classifiers will be developed to
discriminate mildly-active from severely-active CD. In Aim 2, PBE lipids will be examined longitudinally within
individual patients before and after therapy to identify lipids correlate with clinical response. Such information will
also be passed to Aim 1 to develop more robust classifiers. Testing patterns of PBE lipids in responsive and
refractory patients is intended to improve the robustness of the classifiers. Studies in Aim 1 and 2 are greatly
enhanced by the inclusion of a second clinical site (Baylor University) to provide samples to validate (or not) data
from University of Kentucky. The long-term goal will be to justify studies to identify a “exosomal lipid signature”
panel that provide a novel set of biomarkers for discriminating levels of CD disease activity and informing
treatment decisions. We post that the creation of a CD exosome lipid biomarker test will obviate the need for
follow-up endoscopy in the majority of patients.
Status | Finished |
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Effective start/end date | 9/1/18 → 8/31/21 |
Funding
- National Institute Diabetes & Digestive & Kidney: $431,478.00
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