Chapter 4. Diffusion, Metabolic, and Histological Characteristics

Reason: This chapter is currently being prepared to be submitted as a journal manuscript.

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Development of a Mini-Pig Model of Radiation-Induced Brain Injury

thesis
posted on 25.04.2022, 13:59 authored by Whitney PerezWhitney Perez

While radiation therapy is a standard treatment modality for managing primary and metastatic brain tumors, it causes irreversible and progressive long-term side effects that decrease the quality of life for pediatric brain tumor survivors. These side effects, known as radiation-induced brain injury (RIBI) and which occur at least 6 months post-treatment, create challenges in education, employment, and social relationships throughout the patients’ lifetime. With the prognosis for pediatric cancer patients constantly improving, long-term side effects such as RIBI pose a major clinical problem for post-treatment care. To create and evaluate treatments for this clinical injury, it is critical to understand how this condition forms and develops. However, this cannot be done in patients due to the invasive nature of cranial biopsies. The current scientific understanding behind the pathophysiology of these late-delayed forms of RIBI is therefore built upon studies of pre-clinical animal models. Such experimental models, typically of healthy rodents, are not currently capable of accurately replicating the radiological and histological changes seen in human patients. This inconsistency limits the efficacy of preclinical discoveries when translated to clinical trials. To address this issue, we chose to establish a mini-pig model for RIBI using a standard clinical approach of radiation delivery and follow-up imaging. Our hypothesis is that cranial irradiation of the mini-pig brain will elucidate the clinical magnetic resonance imaging (MRI) signatures of RIBI, which will then correspond to characteristic changes in diffusion properties, metabolite profiles, immune constituents, and glial and neuronal cell subpopulations as evidenced by advanced MRI techniques and histopathology. As such, results from Aim 1 have highlighted not only incongruencies between rodent models and clinical findings, but also various inconsistencies in current assessment techniques of late-delayed RIBI in patients. Additionally, results from Aim 2 have established the feasibility of a mini-pig model of RIBI based on the current clinical standard of diagnosis. Finally, results from Aim 3 describe characteristic changes in diffusion properties and histological appearances as well as novel changes in metabolite concentrations within our mini-pig model late-delayed RIBI. In conclusion, this intermediate animal model of RIBI can replicate the clinical condition and may ultimately provide valuable insight into the pathophysiology of RIBI. 

Funding

Indiana Clinical and Translational Sciences Institute

National Center for Advancing Translational Sciences

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Ralph W. and Grace M. Showalter Research Trust

History

Degree Type

Doctor of Philosophy

Department

Health Science

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Ulrike Dydak

Additional Committee Member 2

Keith Stantz

Additional Committee Member 3

Matthew Scarpelli

Additional Committee Member 4

Ilektra Athanasiadi

Additional Committee Member 5

Carlos Perez-Torres