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
Cardiovascular Biology, Cell and Developmental Biology, Neuroscience
Cardiovascular Development and 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 the heart and blood vessels in the developing vertebrate embryo, while simultaneously understanding how these factors are dysregulated in pathological settings in the adult. 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:
1) Defining the transcriptional basis of endothelial organotypic 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) versus the porous, fenestrated endothelium of the liver. The basis for this heterogeneity is unknown. Through transcriptional and epigenetic profiling we have identified a set of core factors present in the vessels of each major organ. We are now focusing on the transcription factors that govern BBB acquisition, and if these same factors can reprogram the functional characteristics of vessels in other organs.
2) The role of RAS/MEK/ERK signaling in brain arteriovenous malformations. We recently found that endothelial-specific, somatic gain of function mutations in KRAS are present in brain arteriovenous malformations: shunts between arteries and veins that lack an intervening capillary network. These shunts are fragile and prone to rupture. 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) Defining the transcriptional regulators of pathologic angiogenesis in glioma.
Excessive endothelial cell proliferation and sprouting are defining features of the deadly adult brain cancer, glioblastoma (GBM). Blood vessels in GBM display structural and functional heterogeneity. We are currently 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.
At the heart of these projects is a concerted effort to identity the transcriptional regulators that endow endothelium with their unique specialized identities and functional characteristics. The long-term objective of our research is to gain a deeper knowledge towards repairing or replacing damaged or diseased vessels, or alternatively preventing exuberant vascularization in disease settings, such as in glioma. To achieve this goal, a detailed mechanistic understanding of how endothelial cell identity is specified and maintained is essential.