Microtubule-Based Therapies for Memory Loss in Gulf War Illness: Studies Using Human Minibrain Organoids from Veteran-Derived Human Pluripotent Cells
Abstract
Overarching Challenges: This proposal is responsive to the Fiscal Year 2020 Gulf War Illness Research Program (GWIRP) Overarching Challenges: Treatments: Eliminate the health consequences associated with Gulf War Illness (GWI) and revolutionize treatment; Determinants: Validate exposures associated with GWI and impacts on organs and systems; Consequences: Determine whether GWI is associated with greater risk for developing other diseases. Objective and Rationale: Gulf War Illness (GWI) is a condition suffered by a third of the nearly 700,000 American Soldiers who served in the 1991 war. These Veterans have symptoms that include persistent headaches, memory and cognitive problems, widespread pain, and fatigue. The illness is believed to have been caused by exposure of the Soldiers to toxicants such as pesticides, anti-nerve gas pills, and nerve gas. There is urgency in solving the mystery of how exposure to the toxicants could cause a long-lasting illness so that future episodes of this kind can be prevented. There is even greater urgency is designing effective therapeutic regimes to treat the Veterans who are currently suffering from GWI, as they have been suffering for many years and their need is immediate. One of the biggest concerns to the Veterans is their ongoing problems with short-term memory. Inside the cells of the nervous system are cells called neurons that extend growths called axons and dendrites. Many axons bundle together to form nerves that send out signals. Dendrites are shorter and are receive incoming information. Axons and dendrites are filled with architectural fibers called microtubules that serve as railroads along which structures inside the axon and dendrite are moved in both directions. If anything detrimental happens to microtubules, axons and dendrite (and the synapses that connect them together) degenerate. Microtubules are known to gradually disintegrate in the brains of patients with Alzheimer’s disease and also in the brains of patients with a one-time blow to the head resulting in traumatic brain injury. Hence, microtubules are extremely important for axons and dendrites but are also extremely vulnerable to disease and injury. A small number of published studies indicate that the chemical toxins believed to cause GWI are detrimental to microtubules. In one published study, a drug that restores a documented microtubule abnormality resulting from the GWI toxins completely restores several cellular defects that may well be the source of the symptoms suffered by the Veterans. The present studies are aimed at ascertaining whether the memory deficits resulting from the toxins might be due to defects in a small number of microtubule-dependent features of the brain that are correctable in this fashion. A key element of the study plan is to use immortalized cultures of cells from the blood of Veterans who are suffering from GWI. To develop these cell lines, a simple blood sample was taken from the Veteran, and then transduced in a special way, using reliable established methods, to make the cells pluripotent – this means that the cells become very much like stem cells, and can be turned into neurons, glial cells, immune cells, or almost any other cell of the body. The same team of investigators who propose to use these cells for the present study developed the cell lines in a previous project funded by the Department of Defense. Cell lines were developed from Veterans of the Gulf War who got sick and also from Veterans who did not get sick, so the two can be compared. The idea was to develop a repository so that any other scientist studying GWI could use the cell lines for their own studies, to maximize the effort of the biomedical community to rush medicines and treatment regimens to the Veterans who are suffering. Now that the cell lines are established, the team will move forward with using them for their own research project on microtubule-based hypotheses. For these studies, the culture
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110537
Entities
People
- Peter W Baas
Organizations
- Drexel University
- United States Army