Application of Proteomics and Electrophysiology to Identify Biomarkers and Targets for CTE Therapeutics
Abstract
Traumatic brain injury (TBI) is unfortunately all too common for the brave men and women who serve our country as well as for civilians. There are very clear immediate effects for TBI ranging from headache and confusion to coma and death; however, there are also longer-term consequences that are often overlooked and not well understood, including the development of Alzheimer s disease (AD) and/or chronic traumatic encephalopathy (CTE). Without knowing how TBI progresses to AD and CTE, we are unable to develop effective tests for tracking disease progression and we are unable to identify possible ways to treat military, Veterans, and civilians suffering from these diseases. Therefore, this proposal focuses on experiments that address the lack of research resources examining how TBI and AD/CTE are connected. One way to determine how neurons, or brain cells, become sick and die from TBI to AD and CTE is to examine how protein levels in these cells differ from the protein levels in normal cells. Proteins are tiny molecules in all of our cells that work to keep cells, tissues, organs, and ultimately our bodies alive and functioning normally. We have previously used cutting-edge technologies to identify proteins important for developing AD (i.e., without a history of TBI) in postmortem human brain. Similarly, we recently performed protein sequencing on a small group of CTE cases and have identified a few promising targets. Therefore, we think that a larger protein sequencing effort on postmortem brain from CTE stages with increasing pathology will provide us with critical insight into disease-related changes. We hope to identify what is driving the abnormal protein (i.e., tau) collections in cells and what ultimately leads to coexisting AD, especially since many subjects with higher CTE stages also have characteristic AD changes. The first aim is to use a mass spectrometer to perform protein sequencing of postmortem human brain from CTE and control cases. We will then use powerful data analysis tools to identify significant protein changes as the pathology increases through the four CTE stages. Since there is also an ongoing effort here at Emory to sequence AD cases through the Accelerated Medicine Partnership-AD grant, we will also use other powerful data analysis tools to compare the CTE and AD datasets to identify additional crucial changes. We will be paying close attention to targets that may affect the protein tau, since tau is likely contributing to brain cell injury. The next aim will be to alter these proteins in cellular models to understand exactly how they may affect cell function, and again, in particular, how the tau protein is impacted. For this proposal, we will study these promising protein targets in human neurons made from induced pluripotent stem cells, which are created by reprogramming human skin cells from consenting adult research volunteers. By using a human cell model, we are hopeful that any promising findings will be more easily translated into markers of disease or therapeutic approaches. For the last aim, we will again alter the proteins in human neurons and determine the effect on electrical activity. Our memory and thinking abilities ultimately depend on normal electrical activity in the brain, so this aim is also critical for understanding the progression from TBI to AD and/or CTE. To accomplish this task, we will alter the significant proteins in human neurons on special dishes and "listen" to the electrical activity with a state-of-the-art microelectrode array recording device. Overall, these studies may identify crucial markers of disease progression and/or proteins that affect tau in the transition period from TBI to AD/CTE. The ultimate goal is to then translate these findings to improve diagnostic testing abilities and develop therapies so as to ease the suffering for military and Veteran communities and beyond.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610535
Entities
People
- Chadwick M. Hales
Organizations
- Emory University
- United States Army