Wythe, Joshua D
Associate Professor, Cell and Developmental Biology
- BA, History, Miami University
- BS, Botany, Miami University
- PhD, Oncological Sciences / Cardiovascular Development, University of Utah School of Medicine
- Postdoctoral Fellowship, Cardiovascular Development and Disease, University of California, San Francisco
Cancer Biology, Cardiovascular Biology, Cell and Developmental Biology, Development, Stem Cells & Regeneration, Genetics, Neuroscience, Translational Science
Cardiovascular Development and Cerebrovascular Pathologies
The cardiovascular system is the first organ system to form in vertebrates and it is essential for embryonic survival. This system continually grows and remodels to meet the increasing energetic demands of the fetus, and it is also essential for maintaining adult homeostasis. Identifying the networks controlling blood vessel and cardiac morphogenesis, and the pathways maintaining their function in adults, are critical for elucidating the mechanisms
underlying congenital birth defects, as well as for developing therapeutics to combat cardiovascular disease: the leading cause of mortality and morbidity in the world.
The main focus of our research is to understand the molecular, genetic, and cellular mechanisms underpinning the formation, function, and maintenance of blood vessels in the developing vertebrate embryo, while simultaneously understanding how these factors are dysregulated in pathological settings in the adult, with a focus on diseases that impact the brain, such as stroke, vascular dementia, and brain cancer. We combine both zebrafish and mouse genetic models together with bioinformatics, functional genomics, and 3D imaging to investigate blood vessel development and pathogenesis. We are currently pursuing three main projects in our laboratory, among others:
1) Defining the transcriptional basis of endothelial plasticity and function.
Vessels of different organs have unique properties, such as the impermeable nature of the brain endothelium (e.g. the blood brain barrier or BBB) versus the porous, fenestrated endothelium of the liver. The basis for this heterogeneity is unknown. Through bulk and single cell transcriptional and epigenetic (ATAC-seq) profiling and informatic analyses we have identified a set of core transcription factors unique the vessels of each major organ. We are now focusing on the transcription factors that govern BBB acquisition, and determining if these same factors can reprogram the functional characteristics of vessels in other organs to make them adopt different functional properties and characteristics.
2) The role of RAS/MEK/ERK signaling in brain arteriovenous malformations.
We recently found that endothelial-specific gain of function mutations in KRAS are present in brain arteriovenous malformations: shunts or abnormal connections between arteries and veins that lack an intervening capillary network. These shunts are fragile and prone to rupture, which leads to intracerebral hemorrhage and possibly death. We are now asking if targeting this pathway can block or reverse these lesions, while also pursuing the mechanisms of KRAS-induced bAVMs at the cellular and molecular level.
3) Identifying novel therapeutic vulnerabilities in glioblastoma.
Excessive endothelial cell proliferation and sprouting are defining features of the deadly adult brain cancer, glioblastoma multiforme (GBM). Our work has demonstrated that blood vessels in GBM display structural and functional heterogeneity. Currently, we determining if developmental angiogenic regulators we’ve identified also regulate pathogenic angiogenesis in this setting, and whether these factors can be targeted to inhibit tumor vascularization, and thus disease progression.
Other projects include modelling vascular dementia in mice, creating novel animal models of lymphatic vessel malformations in mice and zebrafish, and creating novel animal models of inherited and sporadic diseases that feature cardiovascular defects.
At the heart of these projects is a concerted effort to identity the transcriptional regulators and molecular networks that endow endothelium with their unique functional characteristics (such as impressive barrier function of the BBB in the brain). To achieve this goal requires a detailed mechanistic understanding of how endothelial cell identity is specified and maintained and the long-term objective of our research is to gain a deeper understanding of these mechanisms to facilitate the repair or replacement of damaged or dysfunctional vessels, or alternatively prevent exuberant vascularization in disease settings, such as glioma.