Identification of Mechanotransduction Mechanisms Leading to Neuronal Injury in Cerebral Organoids
Abstract
Purpose: The purpose of the proposed study is to determine the mechanisms by which traumatic brain injury causes dementia. We will focus specifically on one form of dementia called frontotemporal dementia (FTD) because this fatal neurodegenerative disease has been linked to traumatic brain injury and FTD is quite amenable to clinical trials to test any resulting therapeutics. This is because physicians can readily diagnose FTD and patients progress rapidly, meaning that clinical trials can be shorter in duration and less expansive than those for slower progressing diseases such as Alzheimer’s. Goal: Our expected outcome for the project will be to (1) determine how traumatic brain injury causes nerve degeneration in health individuals, (2) determine how it accelerates nerve degeneration in people that are genetically predisposed to developing FTD, and (3) identify new potential therapeutic approaches for preventing nerve degeneration after traumatic brain injury. Rationale: Understanding how traumatic brain injury causes nerve degeneration and dementia is the key to developing therapeutics to prevent these outcomes. However, the complexity of the brain and integrated blood supply has made it difficult to understand how brain injury causes nerve degeneration. Moreover, it has been difficult to determine how the genetics of an individual might make them more sensitive to nerve damage after brain injury because live nerve biopsies are difficult to obtain for study in the laboratory. Approach: To overcome these issues, we have developed a new petri dish model of traumatic brain injury that enables the study of human nerve tissue after mechanical injury. This model has the following three important features: (1) it is comprised mostly of nerve cells and therefore enables us to develop a clear understanding of nerve damage after traumatic injury without interference from blood or blood vessel changes; (2) the nerve cells form a three-dimensional tissue, which is critical for mimicking the stiffness and structural properties of the brain that greatly influence the effects of mechanical injury; and (3) the nerve tissue can be derived from both normal individuals or FTD patients who carry disease-causing genes, meaning that we can determine how traumatic injury affects ongoing FTD disease processes in nerve cells. Importantly, we have verified that this new model mimics the types of nerve damage observed after traumatic brain injury, confirming its validity as a model. The proposed study is comprised of two parts. In part 1, we will test our hypothesis that traumatic brain injury causes nerve damage in healthy individuals by activating special receptors on nerve cells that are sensitive to touch. We will also work with our collaborators at Amgen to test 5,000 drug-like chemicals for the ability to prevent nerve damage after traumatic injury. In part 2, we will test our hypothesis that traumatic brain injury in individuals who are genetically predisposed to FTD amplifies and exacerbates the FTD disease processes already existing in nerve cells due to the genetic mutations. Benefits for the Military, Veteran, and Civilian Communities: If successful, our study will establish specialized touch receptors as important therapeutic targets in traumatic brain injury, identify multiple additional therapeutic targets for preventing nerve damage after traumatic injury, and outline therapeutic strategies for preventing injury-induced FTD in individuals with a genetic predisposition. We anticipate that these findings will lead to the development of new therapeutics that prevent dementia caused by traumatic brain injury. If so, this will have an especially large impact on military and Veteran communities who are at risk of or previously experienced traumatic brain injury during military service. Additionally, several lines of work in civilian communities such as construction, athletics, and farming are high-risk for tra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010424
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California