Bioengineered 3D Human Brain Tissues and Animal Models to Investigate the Role of the Microbial Ecosystem in Healthy, Injured and Disease States
Abstract
Recent studies have identified microbial sequences or antigenic epitopes in human brain samples, leading to speculation that microbial factors may play a previously unidentified role in maintaining host tissue homeostasis in the human brain. Comparable to microflora of the intestine, it is speculated that these microorganisms may have a physiological impact on healthy vs. diseased states. However, because brain tissue samples are not easily accessible for investigation in contrast to fecal samples to study the intestinal microbiome, this remains poorly investigated. There is a limited understanding of the potential impacts of the interdependent relationships of human brain ecology and human cognition and disease. For example, disruption to the healthy Òbrain microbiomeÓ by the introduction of foreign microbes and/or a triggering event (e.g., traumatic brain injury (TBI) in a warfighter) may result in impaired cognition and behavior as well as neurodegeneration. Here we propose a multidisciplinary effort to characterize the microbial landscape of the human brain and to utilize these findings to develop a bioengineered in vitro research model as well as relevant in vivo platforms for studying interactions between non-human species (e.g., bacteria, viruses) and the human brain in healthy vs. diseased states. By characterizing the populations of non-human organisms resident in the human brain, and more specifically, the potential impact of altered microbiota resulting from trauma, we will a deliver molecular-level understanding of microbe-specific effects on physical and cognitive performance. These studies will provide a proof-of-concept of how specific microbial communities can impact brain function and will ultimately enable us to leverage these discoveries to develop microbialbased therapeutic interventions. We will combine our state-of-the-art in vitro 3D bioengineered human brain tissue models using our patented human induced neural stem cell (hiNSC) technology, established in vivo platforms of TBI and microbial interventions, and electrophysiological methods to record various in vitro and in vivo models, as well as functional behavioral and cognitive testing. This bottom-up engineering approach combined with established in vivo platforms, functional readouts and assessments of relevant clinical samples will empower us to establish connections across our experimental systems. These insights will provide better understanding of the microbial landscape of the human brain Ð particularly in response to conditions most often affecting military such as TBI. The fundamental knowledge gained through the proposed collaborative projects will ultimately inform strategies for improving treatment outcomes post-brain injury Ð perhaps even through the use of anti-microbial interventions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 28, 2023
- Source ID
- W911NF2310276
Entities
People
- David L. Kaplan
Organizations
- Army Contracting Command
- Tufts University
- United States Army