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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Mcdonald, Cheryl
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Shishina, Anna K; Kovrigina, Elizaveta A; Galiakhmetov, Azamat R et al. (2018) Study of Förster Resonance Energy Transfer to Lipid Domain Markers Ascertains Partitioning of Semisynthetic Lipidated N-Ras in Lipid Raft Nanodomains. Biochemistry 57:872-881
Ivanov, Maxim V; Wang, Denan; Rathore, Rajendra (2018) From Static to Dynamic: Electron Density of HOMO at Biaryl Linkage Controls the Mechanism of Hole Delocalization. J Am Chem Soc 140:4765-4769
Chowdhury, Tamjid A; Koceja, Chris; Eisa-Beygi, Shahram et al. (2018) Temporal and Spatial Post-Transcriptional Regulation of Zebrafish tie1 mRNA by Long Noncoding RNA During Brain Vascular Assembly. Arterioscler Thromb Vasc Biol 38:1562-1575
Prabhudesai, Shubhangi; Koceja, Chris; Dey, Anindya et al. (2018) Cystathionine ?-Synthase Is Necessary for Axis Development in Vivo. Front Cell Dev Biol 6:14
Hopp, Elizabeth E; Cossette, Stephanie M; Kumar, Suresh N et al. (2017) Sucrose Non-Fermenting Related Kinase Expression in Ovarian Cancer and Correlation with Clinical Features. Cancer Invest 35:456-462
Ivanov, Maxim V; Thakur, Khushabu; Bhatnagar, Anshul et al. (2017) Isolation of a chiral anthracene cation radical: X-ray crystallography and computational interrogation of its racemization. Chem Commun (Camb) 53:2748-2751
Talipov, Marat R; Navale, Tushar S; Hossain, Mohammad M et al. (2017) Dihedral-Angle-Controlled Crossover from Static Hole Delocalization to Dynamic Hopping in Biaryl Cation Radicals. Angew Chem Int Ed Engl 56:266-269
Sweeney, Noreena L; Lipker, Lauren; Hanson, Alicia M et al. (2017) Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus. Antibiotics (Basel) 6:
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
Palen, Katie; Weber, James; Dwinell, Michael B et al. (2016) E-cadherin re-expression shows in vivo evidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells. Oncotarget 7:43363-43375

Showing the most recent 10 out of 25 publications