A Human Brain Organoid Platform to Benchmark Biomarkers for Traumatic Brain Injury Severity
Abstract
What is traumatic brain injury and who is affected? The brain is one of the more complex organs in the human body. Neurons, supported by a large number of non-neuronal cells, form intricate wiring networks. These networks control subconscious processes such as breathing and heartbeat, and also enable individuals to move, sense, and process information. Traumatic brain injury (TBI), which occurs when the brain is jolted by an external force, causes brain damage by disrupting these neuronal networks, and often results in declining mental health over time. In theaters of war, Soldiers often experience TBI as a result of blast injury, such as that caused by improvised explosive devices. Because of improvements in armor and battlefield medical care, an increasing number of wounded Warriors survive these blasts. Consequently, serious mental health problems are common among Warfighters and Veterans. Besides military personnel, millions of civilians suffer TBI yearly and may similarly experience debilitating post-traumatic mental health problems. What are the different types of TBI? How is TBI diagnosed and what are some challenges in its treatment? Neurologists classify TBI as mild, moderate, and severe based on an interview with the patient, who will describe whether and for how long she/he experienced symptoms such as headaches, light sensitivity, or memory loss. For severe injuries, brain imaging and blood tests that show evidence of damage to brain cells can help classify injury severity. However, current diagnostic approaches are not perfect, because they can miss microscopic biological changes within the brain cells. These hidden changes, which over time may be responsible for neurological symptoms, can linger and progressively erode the brain. With the hope of better understanding the sequence of biological changes that follow TBI, scientists have simulated TBI in small animals such as rats and mice. These studies have provided valuable clues that partially explain how biological changes in the brain lead to impaired brain function. But, mice are not human, and so they cannot accurately represent how the human brain responds to injury. Thus, there is a need for human models to study TBI. This is crucial to (1) develop new diagnostic tools that accurately assess severity and predict the recovery or decline in brain health over time and (2) understand biological changes in order to aid the design of new therapies that are effective at addressing brain health. How is our team meeting these challenges? Towards these goals, we use human induced pluripotent stem cells (hiPSCs), which are made from a small piece of skin, or a biopsy, from an individual. During the last decade, scientists have learned how to convert hiPSC into any type of cell of the human body. One especially relevant advance is the conversion of hiPSC into three-dimensional spheres ~1-2mm in diameter, called brain organoids. Within organoids, neurons and non-neuronal brain cells form functional neuronal networks reminiscent of the human brain. These miniaturized and simplified models of the brain have been used to model several neurological disorders in a petri dish. Similarly, we propose to use organoids to model TBI of different severities, which has never been done before. Our goal is to demonstrate that organoids are a powerful new model system to help identify those microscopic biological changes caused by injury that are currently missed at the clinic. For this we plan to: (1) quantify key known indicators of structural or biological neuronal damage that accurately distinguish between different severities of injury over time; (2) assess neurological impairment in response to injuries varying in severity; (3) test whether a particular human’s genetic profile makes someone more or less likely to suffer long- term neurological damage; and (4) validate a new potential diagnostic tool that more accurately gauges the extent of micro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210682
Entities
People
- Ester Kwon
Organizations
- United States Army
- University of California, San Diego