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Mechanisms of Late-delayed Radiation Induced Brain Injury: Insights from Extracellular Matrix and Transcriptional Profiling
Başlık:
Mechanisms of Late-delayed Radiation Induced Brain Injury: Insights from Extracellular Matrix and Transcriptional Profiling
Yazar:
Andrews, Rachel N., author.
ISBN:
9780355987010
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (290 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: J. Mark Cline Committee members: Linda J. Metheny-Barlow; Gretchen Neigh; M. Kerry O'Banion; Ann M. Peiffer.
Özet:
Fractionated whole brain irradiation (fWBI), as used for the treatment of intracranial neoplasia, results in progressive cognitive impairment, and cerebrovascular and white matter injury. Although the clinical progression and morphology of late-delayed radiation-induced brain injury (RIBI) are well characterized, the pathogenesis is unclear. The long-term consequences of single high dose irradiation of the adult brain, as may occur following a nuclear accident or malicious exposure, are uncertain.
The purpose of this dissertation was to identify novel pathways and molecular effectors in a non-human primate model of RIBI and to assess if similar changes were present in long-term survivors of single high dose total body irradiation. These aims were evaluated in three separate experiments, presented in Chapters 2-4.
For Chapters 2 and 3, we evaluated brain tissue from four adult male rhesus macaques (Macaca mulatta) that developed RIBI 4-6 months post-fWBI. Changes in gene expression were assessed by RT-qPCR to screen a priori selected pathophysiologic processes. Animals with RIBI demonstrated evidence of microglial/macrophage-mediated neuroinflammation, hypoxia, vascular maturation and stabilization, extracellular matrix (ECM) deposition and remodeling and impaired glutamatergic neurotransmission.
In Chapter 3, we characterized the composition of accumulated perivascular ECM by immunohistochemistry and identified fibronectin as one of the primary components. By in situ hybridization, we determined that cerebral endothelial and vascular smooth muscle cells produce fibronectin in RIBI.
In Chapter 4, we expanded our analyses to evaluate five rhesus macaques which survived 12 months post-fWBI, and five which previously received high dose (6.75-8.05 Gy) TBI, 6-9 years prior to necropsy. RNA-sequencing and subsequent whole transcriptomic gene expression profiling revealed fWBI and TBI resulted in shared transcriptional patterns of CNS injury including neuroinflammation, complement fixation and impaired glutamatergic neurotransmission. fWBI animals also demonstrated increased expression of pathways associated with ECM deposition and remodeling.
In conclusion, cerebral irradiation results in persistent neuroinflammation, expression of complement factors and evidence of impaired glutamatergic neurotransmission in rhesus macaques months to years post-exposure. Perivascular fibronectin accumulation may contribute to RIBI following fWBI. These findings have led to a novel proposed mechanism of radiation-induced brain injury and the identification of several potential therapeutic targets.
Notlar:
School code: 0248
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680917.1) | 680917-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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