Browsing by Author "Heiss, John D."

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    Developmental vascular malformations in EPAS1 gain-of-function syndrome
    (American Society for Clinical Investigation, 2021-03-08) Rosenblum, Jared S.; Wang, Herui; Dmitriev, Pauline M.; Cappadona, Anthony J.; Mastorakos, Panagiotis; Xu, Chen; Jha, Abhishek; Edwards, Nancy; Donahue, Danielle R.; Munasinghe, Jeeva; Nazari, Matthew A.; Knutsen, Russell H.; Rosenblum, Bruce R.; Smirniotopoulos, James G.; Pappo, Alberto; Spetzler, Robert F.; Vortmeyer, Alexander; Gilbert, Mark R.; McGavern, Dorian B.; Chew, Emily; Kozel, Beth A.; Heiss, John D.; Zhuang, Zhengping; Pacak, Karel; Pathology and Laboratory Medicine, School of Medicine
    Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.
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    Multimodal Atlas of the Murine Inner Ear: From Embryo to Adult
    (Frontiers Media, 2021-07-15) Bryant, Jean-Paul; Chandrashekhar, Vikram; Cappadona, Anthony J.; Lookian, Pashayar P.; Chandrashekhar, Vibhu; Donahue, Danielle R.; Munasinghe, Jeeva B.; Kim, H. Jeffrey; Vortmeyer, Alexander O.; Heiss, John D.; Zhuang, Zhengping; Rosenblum, Jared S.; Pathology and Laboratory Medicine, School of Medicine
    The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. Development of this structure from neural crest begins in utero and continues into early adulthood. However, the anatomy of the murine inner ear has only been well-characterized from early embryogenesis to post-natal day 6. Inner ear and skull base development continue into the post-natal period in mice and early adulthood in humans. Traditional methods used to evaluate the inner ear in animal models, such as histologic sectioning or paint-fill and corrosion, cannot visualize this complex anatomy in situ. Further, as the petrous bone ossifies in the postnatal period, these traditional techniques become increasingly difficult. Advances in modern imaging, including high resolution Micro-CT and MRI, now allow for 3D visualization of the in situ anatomy of organs such as the inner ear. Here, we present a longitudinal atlas of the murine inner ear using high resolution ex vivo Micro-CT and MRI.