PROJECT SUMMARY
Radiation therapy (RT) is a standard-of-care oncological treatment for the central nervous system
(CNS). However, during cranial RT, normal brain tissue adjacent to the tumors is inevitably
irradiated, causing transient reversible abnormalities as well as progressive irreversible late
toxicities. Approximately 100,000 patients with primary and metastatic brain tumors per year in
the United States survive long enough (>6 months) to develop radiation-induced brain injury,
including cognitive impairment and/or neurological sequelae, significantly impeding the quality of
life. These symptoms occur in 50-90% of adult patients after treatment and can be seen without
clinical and radiographic evidence of histological changes. In this proposal, we aim to establish a
novel, robust, cell-based 3D brain organoid model that closely mimics the complexity of the
human brain microenvironment, serving as a platform to study pathophysiological processes and
neuroinflammation induced by RT in the normal brain tissue. Further, leveraging the established
UCLA portfolio of radiation mitigators, the brain organoid model could be a promising screening
and testing platform that recapitulates the human brain responses to therapeutic agents. Overall,
this proposal will not only characterize the real-time and dose-dependent physiological responses
of normal brain tissue to ionizing radiation, but will also provide proof-of-principle evidence to
support the use of human brain organoid model as a platform for screening and testing radiation
mitigators, enabling thus the development of adequate countermeasures against radiation.
Considering that patient-derived iPSCs may be leveraged to develop personalized testing models,
our novel biomimetic model holds significant promise in the screening of patient-specific radiation
mitigators in the era of precision medicine in the near future.
