Vascular anomalies (VAs), inborn errors in embryonic vascular development are classified into two distinct groups: hemangiomas and vascular malformations (VMs). Current therapies for VAs are limited in efficacy and have significant complications. Therefore, to improve therapy for patients afflicted with these conditions, it is critical to identify the underlying mechanism leading to pathogenesis of VMs and hemangiomas. Our long-term goal is to understand the underlying mechanisms that lead to pathogenesis of VAs so that better therapeutics targeting this condition can be generated. In order to pursue that goal, the objective here is to study two recently identified genes by our group namely Sucrose non-fermenting receptor kinase-1 (Snrk-1), a serine- threonine kinase, and dual-specific phosphatase-5 (Dusp-5), a mitogen-activated protein kinase (MAPK) family, which are mutated in patients with hemangiomas and VMs. Our central hypothesis is that """"""""transforming growth factor-beta (TGF-) ligand interacts with specific receptors (ALK-1/ALK-5) on endothelial cells transmitting signals via Snrk-1 and Dusp-5 to common substrate Rho-associated, coiled-coil containing protein kinase-1 (Rock-1) to induce specific responses in that cell and cells surrounding it."""""""" This hypothesis is formulated based on preliminary data from our group that identified several members (Alk-1, Alk-2, Smad-3, BMPR-2) of the TGF- signaling family and Rock-1 in a screen for substrates for Snrk-1. The rationale for the proposed research is that once it is determined how Snrk-1 and Dusp-5 modulate TGF- signaling in ECs and EC precursors (angioblasts) during embryonic development, we can target the TGF- Snrk-1/Dusp-5 signaling pathway with repurposed FDA-approved drugs thus providing better target based therapeutic options for VAs patients. The hypothesis will be tested by pursuing three specific aims: 1) Identify the contribution of cell autonomous vs. non-autonomous Snrk-1/Dusp-5 function and the role of Dusp-5 mutations in VA disease pathogenesis. 2) Identify the mechanistic role of Rock-1 in Snrk-1/Dusp-5 signaling in vivo and in vitro. 3) Determine mechanistically how Snrk-1/Dusp-5 participates with specific signaling pathway in vivo and in vitro. In each of these aims, we will employ a variety of cell biology, molecular and developmental biology approaches to unravel the mechanistic underpinnings of Snrk-1/Dusp-5 to TGF- signaling pathway including the role of Rock-1 in this process in vivo and in vitro. The approach is innovative because it provides us an unprecedented opportunity to understand the molecular pathway that these genes participate in vivo thereby contributing to our understanding of the mechanistic steps involved in VAs pathogenesis. The proposed research is significant because studying novel intracellular signaling molecules that participate in the mechanistic underpinnings of the TGF- signaling pathway in vasculogenesis, removes this critical barrier to progress thus moving the field of vascular biology forward.
The proposed research is relevant to public health because vascular anomalies (VAs) represent an important clinical problem that has few therapeutic options. The successful mechanistic understanding of VAs pathogenesis is likely to provide candidate targets for drug development against VAs. Thus, the proposed research is directly relevant to NIH's mission of reducing the burden of debilitating health conditions from diseases affected by deregulated vasculature.
|Rana, Ujala; Liu, Zhong; Kumar, Suresh N et al. (2016) Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice. Dev Biol 410:190-201|
|Cossette, Stephanie M; Bhute, Vijesh J; Bao, Xiaoping et al. (2016) Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function. Circ Cardiovasc Genet 9:474-486|
|Sampath, Venkatesh; Menden, Heather; Helbling, Daniel et al. (2015) SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 135:e1530-4|
|Kilari, Sreenivasulu; Cossette, Stephanie; Pooya, Shabnam et al. (2015) Endothelial Cell Surface Expressed Chemotaxis and Apoptosis Regulator (ECSCR) Regulates Lipolysis in White Adipocytes via the PTEN/AKT Signaling Pathway. PLoS One 10:e0144185|
|Neumann, Terrence S; Span, Elise A; Kalous, Kelsey S et al. (2015) Identification of inhibitors that target dual-specificity phosphatase 5 provide new insights into the binding requirements for the two phosphate pockets. BMC Biochem 16:19|
|Menden, Heather; Welak, Scott; Cossette, Stephanie et al. (2015) Lipopolysaccharide (LPS)-mediated angiopoietin-2-dependent autocrine angiogenesis is regulated by NADPH oxidase 2 (Nox2) in human pulmonary microvascular endothelial cells. J Biol Chem 290:5449-61|
|Schupp, Marcus-Oliver; Waas, Matthew; Chun, Chang-Zoon et al. (2014) Transcriptional inhibition of etv2 expression is essential for embryonic cardiac development. Dev Biol 393:71-83|
|Nayak, Jaladhi; Gastonguay, Adam J; Talipov, Marat R et al. (2014) Protein expression, characterization and activity comparisons of wild type and mutant DUSP5 proteins. BMC Biochem 15:27|
|Wang, Ling; Cossette, Stephanie M; Rarick, Kevin R et al. (2013) Astrocytes directly influence tumor cell invasion and metastasis in vivo. PLoS One 8:e80933|
|Leigh, Noah R; Schupp, Marcus-Oliver; Li, Keguo et al. (2013) Mmp17b is essential for proper neural crest cell migration in vivo. PLoS One 8:e76484|
Showing the most recent 10 out of 17 publications