Friday, May 16, 2025
5/16/2025
Protein tyrosine phosphatase non-receptor 14 in vascular stability and remodeling - ABSTRACT The vascular system is critical to life, infusing each organ of the body with oxygen and nutrients, and transporting and interacting with immune cells that protect the body. In the adult, maintenance of an intact vascular endothelium is under strict homeostatic control to prevent edema or hemorrhage. Wounding or tissue hypoxia can result in angiogenesis and vascular remodeling. The process of vascular homeostasis is highly regulated and involves many molecular players acting in concert. Under disease conditions, orchestration of these molecular processes may go awry. This is especially true in rare Mendelian disorders that are caused by mutations in key components of this machinery, such as Hereditary Hemorrhagic Telangiectasia (HHT), which is caused by loss of function mutations in ENG, ACVRL1, or SMAD4. Understanding the molecular underpinnings that regulate vascular homeostasis is critical to many diseases, including susceptibility to, and recovery from, acute lung injury and COVID-19. Here, we will investigate the role of protein tyrosine phosphatase non-receptor, type 14 (PTPN14) as a critical player in regulation of both blood and lymphatic vessel homeostasis. We previously showed that genetic variation within the PTPN14 gene associates with pulmonary arteriovenous malformations (AVMs) in HHT patients, and human genetics studies suggest a role for PTPN14 in lymphatic development and homeostasis. PTPN14 is an antagonist of YAP signaling and we have shown that it supports ALK1(ACVRL1)/SMAD4 signaling. We have identified several cis-eQTL in the PTPN14 gene that associated with PTPN14 expression and with the presence of pulmonary AVM in HHT, suggesting that PTPN14 expression levels influence AVM incidence. We have also identified two rare non- synonymous PTPN14 SNPs that segregate with AVMs and we will also determine how these affect PTPN14 function and molecular interactions with SMAD4 and YAP/TAZ. We will use human engineered microvessels under flow conditions to investigate the effects of PTPN14 knockdown or mutation, with or without ENG or ACVRL1 knockdown, on endothelial cell, size, proliferation, migration, alignment with flow, and vascular permeability under differing flow conditions. Finally, we will use our Cre-mediated Ptpn14-loxp allele, generated in-house, to investigate development of vascular and lymphatic malformations that result from genetic loss of Ptpn14 in endothelial or parenchymal cells in vivo, and examine how PTPN14 interacts with the BMP9- endoglin-ALK1 signaling pathway to modulate formation of AVMs in vivo. We will generate tamoxifen-inducible cell type-specific Ptpn14-/- and investigate how this affects developmental angiogenesis, pathological angiogenesis in wounded cornea, and vascular beds of adult lung, skin, liver, gut and brain. We will also investigate the effects of Ptpn14DiEC on Eng+/-, EngDiEC phenotypes to determine how these genes interact in vivo. Blood flow in the lung and potential arteriovenous malformations will be assessed using our new Quantum GX2 micro-CT imager obtained through an S10 grant.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).