Scientific Rationale: Many findings point to a key role for membrane changes in Gulf War Illness (GWI). (1) Gulf-exposures, e.g., pesticides and radioactive chemicals (depleted uranium), are known to alter membrane composition/properties. (2) In “Metabolomic” (MO) testing (of multiple biochemical markers in the blood together), all “metabolites” altered in GWI (vs. controls) are known to govern membrane structure/function and/or be affected by membrane properties. (3) Several findings supported low levels of “arachidonic acid” (AA) in membranes in GWI. (a) “Prostaglandins” and “leukotrienes,” made in membranes from membrane AA, are low in GWI. (b) Levels of “MDA,” also made from AA, correlate with membrane AA and are low in GWI. (Of note, membrane changes and low MDA have been reported following a GW-relevant exposure.) (4) Consistent with this, low membrane AA is reported to depress mitochondrial function -- which is reported in GWI. (5) Mitochondrial membrane changes regulate programmed cell death -- called “apoptosis” -- which was altered in GWI in each of three GWI gene expression studies. (6) Membrane changes are tied to coagulation activation and to (7) postural tachycardia (increased heart rate rise with standing up, from lying down) -- both of which are reported in GWI. (8) In a prior GWI proposal, based on MO findings that suggested membrane changes in GWI, we suggested a therapy (that we cited) targeted to membrane health might benefit those with GWI. A GWI advocate later circulated an email stating that Veterans with GWI were benefiting from this therapy.

Together, these findings support high prospects for a critical role for membrane changes in GWI. They support a role for membrane changes in health in GWI. They affirm that membrane changes offer targets for treatment in GWI. They even suggest this promise is beginning to be realized. Membranes assessment in GWI is clearly due.

The study proposes to pioneer the understanding of membrane changes in GWI. This may lead to new objective markers in GWI. It may explain mechanisms and outcomes shown to be altered in GWI (e.g., provide a basis for impaired mitochondrial function, apoptosis, coagulation activation, postural tachycardia), providing a mechanism upstream to these (that is, a mechanism that may serve as the foundation for the other mechanisms).

Objective: To assess differences in membrane characteristics -- for both cell membranes and mitochondrial membranes -- in GWI vs. matched controls. We will assess membrane fluidity/viscosity, composition, voltage difference across the membrane, appearance under the microscope, and membrane resilience (ability to repair following damage). To get cells for membrane testing, a small biopsy of the skin will be taken. Cells (“fibroblasts”) will be grown (“cultured”). These have been effective for identifying membrane changes tied to health outcomes. Membrane changes affect many things relevant to GWI, e.g., mitochondrial function, nutrient uptake into cells, hormone production, cell signaling, cell function, and cell death. A scientist expert in membrane assessment will perform the membrane testing. Membrane properties will be compared in Veterans with GWI vs. controls. We will assess whether/how Gulf and non-Gulf exposures predict membrane alterations and how membrane alterations relate to GWI symptoms and rise in heart rate with standing (“postural tachycardia”).

Veteran and Control Experience: Eligible and interested Veterans and controls will share their symptoms and exposures and give a small blood sample. Heart rate and blood pressure will be measured -- lying down, then standing up -- since high heart rate rise with standing is common in GWI, and has been linked, outside the GWI setting, to altered membrane properties. A small (3 mm diameter) sample of skin will be taken from the back of the upper arm, under local anesthesia so that the procedure should be painless.

Impact: This study has a chance to radically shift our understanding of GWI. Many forms of evidence show high likelihood of membrane changes in GWI. Such changes may explain many mechanisms and outcomes altered in GWI. Understanding membrane changes has exceptional promise to lead to treatments that may transform the lives and health of Veterans with GWI. As a further benefit, the matched GWI and control cell lines created in this study will be frozen and banked, available to future studies. These samples can be thawed and re-expanded (grown into more cells), or “regressed” to stem cells from which many cell types can be grown.