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Study of Thrombospondin-1 (TSP1) in ME / CFS pathogenesis (STOP-ME)

Study Aim

This study aims to understand the role of TSP-1 in the pathophysiology of ME/CFS and how that role may provide insight into more effective use of pharmacological interventions.

LEAD INVESTIGATORS
  • Alain Moreau, PhD
Results / Reason for Discontinuation
  • Application of a stress-test revealed a different physiological behavior of ME/CFS patients along three clusters (as defined initially with our diagnostic panel of circulating microRNAs).
    • Cluster 1 encompasses ME/CFS patients showing no significant changes in TSP-1 blood level after stimulation versus the baseline values.
    • Cluster 2 encompasses ME/CFS patients showing a drastic reduction in TSP-1 levels following the stress-test and corresponds to patients exhibiting an orthostatic intolerance with or without POTS.
    • Cluster 3 encompasses ME/CFS patients showing a strong elevation of TSP-1 blood levels after the application of the stress-test. This group corresponds to those with brain fog and more severe PEM.
  • Our preliminary experiments showed that exposition to TSP-1 proteins inhibits the signaling of membranous receptors, termed GPCR, when they are coupled to G inhibitory proteins (Gi). This discovery is important because it could explain neuroendocrine symptoms in ME/CFS patients having high circulating TSP-1 levels.
  • The identification of a receptor interacting with TSP-1 could allow us to propose a therapeutic approach to relieve, prevent, or reduce “brain fog” and related symptoms in ME/CFS patients. Interestingly, α2δ-1 is the high affinity receptor for two commonly prescribed anti-epileptic, anti-neuropathic pain medications, gabapentin (NeurontinTM) and pregabalin (LyricaTM). Both drugs are being used off-label for ME/CFS and fibromyalgia patients, mostly for pain relief but some patients also report significant improvement of their “brain fog” and neurocognitive symptoms.
  • Search for the mechanisms causing the elevation of TSP-1 secretion and production in ME/CFS led us to explore a possible connection between the IDO2 metabolic trap given than inactivation of IDO2 by common mutations could increase tryptophan (Trp), an amino acid, at the cellular level. It is well known that such an increase could lead to the elevation of proteins like TSP-1 due to their high content in Trp as a defense mechanism to prevent Trp accumulation, which could be toxic.
  • Among other possible mechanisms, leading to higher TSP-1 levels, we intend to investigate if hyperglycemia and glucose intolerance could lead to an increase in TSP-1 levels in some ME/CFS patients.
  • The next phase of our investigation continued with the MAESTRO project.

Study Hypothesis and Description

Little is known about the mechanisms causing brain fog, orthostatic intolerance, and postural orthostatic tachycardia (POTS) in ME/CFS. These vascular instabilities are part of a group of symptoms affecting many people with ME/CFS, and current treatment strategies to alleviate are limited and often not very effective. In that context, we used our previously developed method with a specific stress-test to identify possible biomarkers that could be involved in the onset and/or progression of the symptoms associated with these specific vascular instabilities.

We propose that elevation of circulating thrombospondin-1 (TSP-1), a multifunction protein, in the blood could reduce brain-blood flow in some persons suffering from ME/CFS leading to a brain fog and post-exertional malaise (PEM). Conversely, a rapid decrease in TSP-1 blood levels in some ME/CFS patients could induce hypotension, resulting in orthostatic intolerance or even POTS.

Objectives

  • Identify physiological behavior of ME/CFS through a stress test, and correlate that behavior with TSP-1 levels in the blood.
  • Evaluate the mechanism of TSP-1 secretion and production in ME/CFS.

Other links you might be interested in:

Melbourne ME/CFS Collaboration
University of Montreal Collaborative Research Center
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2024 YEAR END REPORT

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Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia Leading Research. Delivering Hope.Open Medicine Foundation®

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