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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® Canada
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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.

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Microvesicles and viral sequencing
Microvesicles are a type of extracellular vesicle that is released from the cell membrane. Vesicles are small, fluid-filled sacs or vacuoles within the body. Sequencing is a technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA (or viral) molecule.
NMR Metabolomics
NMR (Nuclear Magnetic Resonance) is an instrument/tool used to perform metabolic studies, metabolic profiling, and metabolomics in biofluids and tissues for more than 40 years using magnetic fields. There is a very close connection between metabolic measurements and NMR. This connection has flourished because of NMR’s many unique strengths for characterizing complex mixtures’ chemical composition.
Proteomics
The large-scale study of proteins, which are large, complex molecules that are required for structure, function, and regulation of the human body's tissues and organs.
Autoantibodies
Antibodies that react with self-molecules and that occur in healthy individuals and are referred to as natural antibodies or autoantibodies.
Extracellular DNA for viral reactivation and Mitochondrial DNA
exDNA (extracellular DNA), exDNA is often secreted actively and is used to perform several tasks, thereby offering an attractive target or tool for biotechnological, medical, environmental, and general microbiological applications. Viruses are intracellular parasites that rely to a significant extent on the host cell for replication. Viral reactivation occurs when an active replication of the viral genome results in a lytic (degradation of the cell) infection characterized by the release of new progeny (descendant) virus particles.
Immune cell profiling
The immune system has many important regulatory roles in disease development and progression. Given the emergence of effective immune therapies, reliable predictors of response are needed. Immune cell profiling determines response by evaluating immune cell populations from treated and untreated samples. For our purposes, we will evaluate the white blood cell response to the viral infection using a process called “Cytof.”
Leukocyte Genomics
A leukocyte is a colorless cell circulating in the blood and body fluids and is involved in counteracting foreign substances and disease. A genome is all genetic material of an organism. Genomics is a biology field focusing on the structure, function, evolution, mapping, and editing of genomes. Therefore, leukocyte genomics is the study of all genetic material of leukocytes.
Metabolomics
Metabolomics is a way to study metabolism – that is, through measuring amounts of the metabolites (small molecules) produced by our bodies as we convert food into energy and other molecules that our cells need to survive. Metabolomics technology is ‘large-scale,’ meaning that several thousand metabolites can be measured from a single sample of e.g., blood or urine.
Micro RNA
Cells use Micro RNA to control whether a particular gene is making too much, too little or the normal amount of its protein at a particular time.