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 find new drugs or repurpose FDA-approved drugs to target VAs. 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 is to identify small molecules (SMs) that will target dual-specific phosphatase-5 (Dusp-5), a member of the mitogen-activated protein kinase (MAPK) family, which is mutated in patients with hemangiomas and VMs. We have identified a serine to proline mutation at 147 AA in DUSP-5 (S147P), which results in a hypoactive phosphatase that is unable to dephosphorylate p-ERK. This results in sustained p-ERK levels, which is often associated with increased proliferation of cells such as those in VAs. Our central hypothesis is that, "human S147P protein recapitulates zebrafish S148P protein function, whereby mutation perturbs the interaction with p-ERK such that DUSP5 phosphatase domain (PD) cannot be properly positioned to de-phosphorylate p-ERK. Small molecules such as SM1842, FDA-approved compounds (Suramin), and SM1842 analogs can reverse this effect, thereby permitting a switch between WT and S147P function both at the molecular level (in vitro), and in terms of cellular function." This hypothesis is formulated based on preliminary data from our group that predicts the incorrect positioning of the DUSP5 PD domain in relation to p-ERK using computational modeling studies on Dusp-5 interaction with ERK, which suggests the molecular mechanism that leads to the S147P

Public Health Relevance

The proposed research is relevant to public health because vascular anomalies (VAs) represent an important clinical problem that has few therapeutic options. The successful development of a small molecule or FDA- approved compound that targets mutated Dusp-5 over WT Dusp-5 protein will provide the much needed therapy alternatives for patients with VAs. Thus, the proposed research is directly relevant to NIH

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112639-01
Application #
8259361
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Mcdonald, Cheryl
Project Start
2012-02-21
Project End
2016-12-31
Budget Start
2012-02-21
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$505,927
Indirect Cost
$114,813
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
McCullough, Christopher; Neumann, Terrence S; Gone, Jayapal Reddy et al. (2014) Probing the human estrogen receptor-* binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study. Bioorg Med Chem 22:303-10
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
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
Span, Elise A; Goodsell, David S; Ramchandran, Ramani et al. (2013) Protein structure in context: the molecular landscape of angiogenesis. Biochem Mol Biol Educ 41:213-23