Driving research of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS),
Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia and Post COVID .

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Multi-omics of iCPET Plasma Samples

STUDY AIM

This project aims to understand the origin of postural orthostatic tachycardia syndrome (POTS).

LEAD INVESTIGATORS
  • Wenzhong Xiao, PhD
  • David Systrom, MD
  • Richard Smith, PhD
  • John Jacob, PhD
  • Wei-Jun Qian, PhD
UPDATES AND POTENTIAL
The multi-omics iCPET study of exercise intolerance has been conducted. iCPET was performed on 20 ME/CFS patients and 10 controls. Blood plasma samples were collected before, at the peak, and after the cardio-pulmonary exercise test from the arterial and the polled venous blood of each subject. The samples were processed and analyzed in four omics analyses: (1) inflammasome (cytokine response to exercise) at NIH, (2) metabolome by Metabolon, (3) high-throughput proteomics by Pacific Northwest National Laboratories (PNNL), and (4) high-throughput proteomics by SomaLogic.

STUDY HYPOTHESIS AND DESCRIPTION

POTS is one of the more common symptoms of ME/CFS. This syndrome appears to involve the cardiopulmonary and peripheral vascular systems, both are modulated by the autonomic nervous system. It is unclear why these systems become dysfunctional to cause POTS but understanding the biological pathology underlying it will be relevant to helping understand its relationship to ME/CFS.

Cardiopulmonary exercise testing together with direct measurement through invasive arterial catheters (iCPET) has been useful to define the reason for unexplained dyspnea in general populations thought to be heart or lung in origin. Using this same diagnostic tool, ME/CFS patients have been evaluated and found to demonstrate a preload failure (PLF) pattern under maximum exercise. There are two forms of this PLF that has been observed: low flow and high flow. The low flow phenotype appears to be consistent with a failure of the autonomic nervous system to shift blood from the venous to the arterial side of the circulation or another possibility is a reduced total blood volume. On the other hand, the high flow phenotype appears as an arterial to venous shunt in the peripheral circulation or another possibility is a reduced oxygen delivery to peripheral circulatory beds or a reduced utilization by the mitochondria. 

 OBJECTIVES

A blood tissue repository has been underway at the BWH for ME/CFS patients undergoing iCPET for many years and blood is available to study 84 ME/CFS patients (all with POTS) and 30 healthy participants for comparison. These blood samples are obtained before, during peak, and one hour after an iCPET procedure and will undergo analysis by proteomic, phospho-proteomic, and metabolomic methods. 

Phospho-proteomics is an analysis form yet to be conducted on ME/CFS patient samples. Plasma proteomics have been conducted in ME/CFS patients but always at rest and not under stress exercise conditions when fatigue and exercise-induced differences are most likely to become evident. 

Read more at the Harvard site 

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.
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.
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.
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.