Activating Transcription Factor 3 Is a Biomarker for Spinal Cord Injury with Neuroprotective Function
Abstract
Objectives (1) Our goal is to determine if ATF3 in blood or cerebrospinal fluid as a biomarker for spinal cord injury (SCI), with which clinician can diagnose how severe the injury is and how well the patient can recover. (2) As our previous work have shown ATF3 is required for recovery after SCI, another goal of the project is to investigate if more ATF3 signals can lead to better recovery after injury using genetically modified animals. Rationale: SCI is a devastating condition that can cause significant functional disabilities, including loss of ability to move and sensation below the injury. There are approximate 294,000 SCI patients and 17,810 new injuries every year in the U.S., and nearly 42,000 Veterans with SCI are treated in VA medical system. Annual SCI costs are estimated to be as enormously high as $9.7 billion and lifetime cost per patient is between $1.2 to $5.1 million. However, currently there is still no effective therapy for SCI, partly because clinical trials in acute SCI are challenging. Compared to more prevalent medical problems such as diabetes or heart diseases, SCI patient population is relatively small; therefore, it is difficult to enroll enough patients to test the therapies. Because the injury level and severity can differ significantly among SCI patients, it is also challenging to evaluate if the treatment is effective. Although the International Standards for Neurological Classification of Spinal Cord Injury score, one of the functional examinations for SCI patients, is the gold standard test, it could be not reliable if the patient is intoxicated or uncooperative. Imaging test such as magnetic resonance imaging (MRI) may not be sensitive enough under certain circumstance. Therefore, it is urgent to identify new reliable biomarkers that allow clinicians to objectively evaluate SCI patients’ initial severity, monitor how injury progresses, and patients’ response to treatment. In SCI, scientists have worked hard to investigate biomarkers for SCI patients, but with little success. Markers of different cell types in spinal cord, as well as molecules in blood cells, have been tested. However, none of the biomarkers currently being studied in SCI are specific to the injured neurons, a major spinal cord cell type that determine the function of spinal cord. In fact, there is even no reliable and specific marker for these injured neurons, although it is one of the major changes in spinal cord tissue after injury. In our preliminary study, we analyzed tens of thousands of genes in spinal cord and found that activating transcription factor 3 (Atf3) is increased as early as 4 hours after SCI. Interestingly, further study showed that ATF3 is only increased in injured neurons, but not other cell types 1 day after SCI. More importantly, we found that ATF3 levels are detectable and elevated in blood and spinal fluid (outside spinal cord) in mouse model of SCI. We then further test it in our human blood samples from our BASIC (Brain and Spinal Injury Center) TRACK-SCI (Transforming Research and Clinical Knowledge-SCI) patient group and observed the serum ATF3 levels are increased in our SCI patients 24 hours post-injury (n=33), compared to healthy volunteers (n=7) and patients with non-SCI trauma groups (n=7). And there is clear correlation between ATF3 blood levels and SCI injury scores (i.e., AIS grades). These preliminary results strongly suggest that ATF3 has the potential to be a clinical biomarker for acute SCI. Applicability and Impact: Our proposal has the potential to help patients with spinal cord injury. Since the samples can be obtained with regular blood draw, it doesn’t pose any additional risk to the patients. It is particular useful to military forces at the battlefield where advanced and delicate imaging test equipment (e.g., MRI) is not available. If proven effective for ATF3 as biomarker for SCI, it can help the clinicians quickly diagnose the severity o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210930
Entities
People
- Jonathan Pan
Organizations
- United States Army
- University of California, San Francisco