Aberrant growth of blood vessels termed 'angiogenesis' contributes to the pathology of several human diseases ranging from macular degeneration, retinopathy to inflammation and cancer. Recently small RNAs encoded in the genome termed microRNAs have been implicated in the regulation of diverse physiological processes including angiogenesis. We recently profiled microRNAs during activation of endothelial cells and identified microRNA-132 as a critical regulator of p120RasGAP during pathological neovascularization. In this proposal, I will characterize the role of miR-132/p120RasGAP in cell survival during stress responses in the vasculature using in vitro and in vivo angiogenesis models during the mentored phase. Using these models, in the independent phase, I will analyze the contribution of a different microRNA that functions as a negative regulator of cell survival in vascular cells. These studies will elucidate how distinct microRNA programs govern the balance between the pro and anti-angiogenic states in the vasculature during development and disease.

Public Health Relevance

While the role of specific microRNAs (miR) in promoting endothelial activation has been well characterized, it is not clear how miRs regulate endothelial survival and apoptosis. In this proposal, during my K99 phase, I will address the role of angiomiR miR-132 in regulating cell survival in the vasculature. In the independent phase, I will analyze the contribution of a pro-apoptotic miR, miR-34 in mediating cell death in the vasculature and its effects on the Notch signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL112962-05
Application #
9047313
Study Section
Special Emphasis Panel (NSS)
Program Officer
Galis, Zorina S
Project Start
2014-05-01
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Chatterjee, Namita; Rana, Shushan; Espinosa-Diez, Cristina et al. (2017) MicroRNAs in Cancer: challenges and opportunities in early detection, disease monitoring, and therapeutic agents. Curr Pathobiol Rep 5:35-42
Wilson, RaeAnna; Espinosa-Diez, Cristina; Kanner, Nathan et al. (2016) MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment. Nat Commun 7:13597
Advani, Sunil J; Camargo, Maria Fernanda; Seguin, Laetitia et al. (2015) Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nat Commun 6:8154
Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68
Anand, Sudarshan; Coussens, Lisa M (2014) Manipulating microRNAs to regulate macrophage polarization in gliomas. J Natl Cancer Inst 106: