Hemoglobin Metabolites and Mitochondrial Dysfunction in Traumatic Brain Injury

This career development award will be supporting Dr. Samuel Shin’s development as an independent scientist focused on iron associated mitochondrial injury in the setting of TBI. Dr. Shin has been a an extremely productive graduate student and medical trainee conducting research in the field of TBI, but in the last 3 years as a junior faculty he has been focused on developing a new pathway that will allow him to uniquely contribute to the scientific community. This current plan will help him build his specialty as a mitochondrial and iron associated oxidative stress expert in TBI. He will gain technical expertise in flow cytometry, transgenic techniques using adeno-associated virus to study development of secondary brain injury, and immunohistochemistry to understand iron metabolism changes after TBI. This will be further supplemented by formal didactics in mitochondrial biology, redox physiology, biostatistics, ethics, and grant writing. This career development effort will be overseen by a mentoring team by faculty from University of Pennsylvania and Children’s Hospital of Philadelphia composed of Dr. Todd Kilbaugh (mentor), a renowned critical care physician who is an expert in brain injury and mitochondrial physiology and Dr. Frances Jensen (co-mentor), an expert in neural plasticity and neurodegeneration. Additionally, he will have four advisors: Dr. Ramon Diaz-Arrastia, a thought leader in TBI therapeutics and biomarkers, Dr. Douglas Wallace, a renowned leader in the field of mitochondrial physiology and genetics, Dr. Rajiv Ratan, an expert in the field of ferroptosis and iron metabolism at Weill Cornell School of Medicine, and Dr. Sharon Xie who has extensive experience in training fellows and junior faculty in biostatistics. The PI (Shin), will also be supported by exceptional resources and faculty at the University of Pennsylvania and Children’s Hospital of Philadelphia for TBI research. The objective of this project is to demonstrate that hemoglobin byproducts and iron leads to mitochondrial dysfunction and subsequent secondary injury. The central hypothesis is that TBI associated hemorrhage leads to accumulation of hemin, which induces accumulation of mitochondrial iron leading to exacerbation of TBI- induced mitochondrial oxidative stress, cell death, and behavioral impairment. To investigate this novel pathophysiological mechanism, the PI proposes to use multiple genetic manipulation techniques to mitigate mitochondrial iron overload and oxidative stress. Specifically, mitochondrial ferritin will be expressed using AAV in mice prior to TBI. Also, mitochondrially directed antioxidants will be expressed, such as mitochondrial glutathione peroxidase-4, periredoxin-3, and mitochondrial catalase to assess for the role of each antioxidant function in TBI. Project Number: 1K08NS144606-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Samuel Shin | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $233,847 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 CN-V (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371519