Email

joshua.wythe@bcm.edu

Positions

Associate Professor

Integrative Physiology
Baylor College of Medicine
Houston, TX US

Associate Professor

Department of Neurosurgery
Baylor College of Medicine

Research Member

Dan L. Duncan Cancer Center

Member

Cardiovascular Research Institute
Baylor College of Medicine
Houston, Texas United States

Addresses

Department of Integrative Physiology (Office)

Baylor College of Medicine
Houston, TX 77030
United States

Education

BA from Miami University

05/2001 - Oxford, Ohio United States

History

BS from Miami University

05/2001 - Oxford, Ohio United States

Botany

PhD from University of Utah School of Medicine

10/2007 - Salt Lake City, Utah United States

Oncological Sciences / Cardiovascular Development

Post-Doctoral Fellowship at University of California, San Francisco

01/2014 - San Francisco, California United States

Cardiovascular Development and Disease

Professional Interests

• Cardiovascular Development
• CNS Vascular Development and Disease
• Brain Arteriovenous Malformations
• Angiogenesis in Glioma
• Transcriptional Regulation of Organogenesis
• Mouse, Zebrafish, and Human Genetics

Professional Statement

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.

Websites

Selected Publications

• Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D, DiStefano PV, Cui M, Chen Z, De Ruiz KB, Schexnayder TS, Ward CS, Radovanovic I, Wythe JD. "Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling." Circ Res. 2020; Pubmed PMID: 32552404
• Carlson JC, Cantu-Gutierrez M, Lozzi B, Huang-Hobbs E, Turner WD, Tepe B, Zhang Y, Herman AM, Rao G, Creighton CJ, Wythe JD, Deneen B. "Identification of diverse tumor endothelial cell populations in malignant glioma." Neuro Oncol.. 2020; Pubmed PMID: 33367832
• Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S,.....Herman AM, Krings T, Andrade-Barazarte H, Tung T, Valiante T, Zadeh G, Tymianski M, Rauramaa T, Ylä-Herttuala S, Wythe JD, Antonarakis SE, Frösen J, Fish JE, Radovanovic I. "Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain." N Engl J Med.. 2018; Pubmed PMID: 29298116
• Wang K, Zhao S, Liu B, Zhang Q, Li Y, Liu J, Shen Y, Ding X, Lin J, Wu Y, Yan Z, Chen J, Li X, Song X, Niu Y, Liu J, Chen W, Ming Y, Du R, Chen C, Long B, Zhang Y, Tong X, Zhang S, Posey JE, Zhang B, Wu Z, Wythe JD, Liu P, Lupski JR, Yang X, Wu N. "Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM)." J Med Genet.. 2018; Pubmed PMID: 30120215

Funding

Decoding the Molecular and Cellular Mechanisms of Mutant KRAS-driven Brain Arteriovenous Malformations - #R01HL159159

$672,007.00 (04/01/2022 - 03/31/2026)

Grant funding from NIH

Targeting Endothelial transcriptional networks in GBM - #IIRA RP200402

(06/01/2020 - 05/30/2023) Grant funding from CPRIT

Velcro AAV Vector for tissue-specific delivery of genome editing reagents with enhanced cargo capacity - #1UG3 TR002865-01

(07/01/2019 - 06/30/2023) Grant funding from NIH

Defining the role of the RAS pathway in brain arteriovenous malformations - #W81XWH-18-1-0350

(07/15/2018 - 07/14/2021) Grant funding from Department of Defense