Bioengineered Intestines Can Evaluate Neuroimmune Pathobiology of Gulf War Illness-Related Gastrointestinal Dysfunction
Abstract
Overarching Challenge: The goal of this proposed project is to create an engineered platform that mimics gastrointestinal (GI) disturbances observed in Gulf War Illness (GWI) Veterans. During their service in the Persian Gulf War (PGW), the compound pyridostigmine bromide (PB) was used to protect troops from toxic effects of nerve agents. Over the years, however, large-dose PB exposure has been associated with illness in PGW Veterans. The proposal directly addresses the overarching challenges of determinants and subtyping, i.e., our studies will directly link exposure to the compound PB to GI dysfunction. We will isolate and study the intestine alone, to determine the specificity of symptoms resulting from acute PB exposure to intestinal dysfunction. Objective and Rationale: Disruptions in intestinal function is a major unexplained occurrence in PGW Veterans that suffer from GWI. There are also no clinical trials that develop therapeutics to improve intestinal function in GWI, partly because there is very limited understanding of how intestinal dysfunction even occurs as a result of GWI/PB exposure. Rodent models of GWI are frequently used to study other symptoms associated with GWI, but it is exceptionally hard to isolate and link the effect of PB exposure to intestinal dysfunction in whole animal models. Our approach involves using these rodent models that demonstrate GWI symptoms, but then further isolate the colon (part of the intestine) and break it down to its cellular components that are responsible for intestinal movement. These cells include: (i) the smooth muscle cells of the colon, (ii) the nerves that are a master regulator at controlling muscle function, and (iii) local immune cells called macrophages. We believe that by reverse engineering the colon from its cellular components, and comparing those from GWI animals and non-GWI animals (control, mimicking healthy people), we can study how PB exposure changes the cells that are directly responsible for mediating intestinal function. In addition to this, we will also get a picture of how immune first-responders like macrophages contribute to this process of intestinal dysfunction. Applicability: Our approach will create the first in-lab (in vitro) model of GWI-related intestinal dysfunction, completely reverse engineered from cellular components of the colon. By using this model, we can study the precise mechanisms by which PB exposure causes intestinal dysfunction, potentially identifying new avenues of therapy for PGW Veterans. Importantly, the bioengineered GWI model will also allow us to screen said therapeutics in the lab with high efficiency and predictive potency, accelerating the time for new compounds to reach the clinical testing stage. Another novel direction we expect this research to take in the future is the possibility of using a patient’s own intestinal stem cells to promote better intestinal function, as a means of stem cell therapy. Overall, we anticipate that successful completion of our proposed studies will positively impact PGW Veterans quality of life within the next 5-10 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110477
Entities
People
- Shreya Raghavan
Organizations
- Texas Engineering Experiment Station
- United States Army