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Radu V. Stan, MD, PhD

Title(s):
Associate Professor of Biochemistry and Cell Biology
Associate Professor of Pathology and Laboratory Medicine

Additional Titles/Positions/Affiliations:
Director, Optical Cell Imaging Facility, Co-Director, Irradiation, Pre-clinical Imaging and Microscopy Shared Resource, Norris Cotton Cancer Center, Lebanon, NH

Department(s):
Biochemistry and Cell Biology
Pathology and Laboratory Medicine

Education:
M.D. 1993 - Cluj, Romania
Postdoctoral, 1994-1999 at University of California San Diego Medical (Advisor George E. Palade)
Ph.D. 2013 - Groningen, The Netherlands

Programs:
Heart and Vascular Research Center
Norris Cotton Cancer Center
Program in Experimental and Molecular Medicine

Websites:
http://www.dartmouth.edu/~radustan/

Contact Information:

Geisel School of Medicine at Dartmouth
Department of Biochemistry and Cell Biology
One Medical Center Drive
Lebanon NH 03756

Office: Rubin 623
Phone: 603-650-8781
Fax: 603-653-9952
Email: Radu.V.Stan@Dartmouth.edu


Professional Interests:

Our laboratory studies the biology of endothelial cells related to cardiovascular function in normal undisturbed tissues as well as in adaptive and pathologic processes underlying inflammatory diseases and cancer.

Our efforts are currently focused on several distinct but interactive project areas, relying on a wide array of experimental approaches including electron microscopy, fluorescence live cell imaging, biochemical, cell biological, genetic and whole animal physiology approaches. These current focus areas are:

1) Cell biology of the endothelium: The laboratory studies how, on one hand, fundamental mechanisms of signaling and membrane traffic control endothelial cell differentiation and organization in different vascular beds. Specific endothelial structures (fenestrae, transendothelial channels, vesiculo-vacuolar organelles, caveolae and other vesicular carriers) have been shown to mediate the exchanges between blood and tissues. Our laboratory has cloned and characterized Plasmalemma Vesicle Associated Protein (PLVAP) gene, whose gene product, the PLVAP/PV1 protein, is the first known component of the endothelial stomatal and fenestral diaphragms, present on the endothelial structures involved in permeability. Taking advantage of PV1 we are currently trying to understand the biogenesis, cellular function and regulation of the endothelial structures involved in transendothelial exchange.

2) Pathways of exchange between blood and the interstitial space: We are particularly interested in elucidating the molecular mechanisms involved in the transendothelial exchanges between the blood plasma and the interstitial fluid in health and disease. We are using genetically engineered mice generated in the lab to understand the precise role of vesicular trafficking as well as the role of endothelial microdomains such as transendothelial channels, fenestrae and vesiculo-vacuolar organelles in microvascular permeability.

3) Role of PV1 in inflammation: PV1 is unregulated on the activated endothelium in inflammatory lesions. Downregulation of PV1 results in blunted diapedesis of leukocytes, which prompted studies as to the precise mechanism by which PV1 participates in this process.

4) Role of PV1 in cancer: Previous work has shown that PV1 is expressed in most, if not all, solid tumor vessels. We have shown that intratumoral deletion of PV1 results in impaired tumor growth, which prompted studies as to the precise mechanism by which PV1 promotes tumor formation and growth.



Keywords: Inflammation, cancer, angiogenesis, microvascular permeability endothelial differentiation, endothelial cell biology, endocytosis, transcytosis, fenestrae, caveolae, transendothelial channels.

Rotations and Thesis Projects:

1. Determine the role of PV1 in inflammation.
2. Determine the role of PV1 protein in cancer. We are employing multiple cancer models to study the role of PV1 in tumor growth.
3. Development of anticancer diagnostics and therapeutics.
4. Characterize the role of PV1 and its interacting partners in the biogenesis and function of caveolae and fenestrae. Determine the roles of these endothelial structures in vivo.

Grant Information:

1S10OD021616
1R01GM120592
16GRNT27260362

Courses Taught:

PEMM 101
PEMM 102
PEMM 275
PEMM 126

Biography:

Dr. Stan did his postdoctoral training 1994-1999 at University of California San Diego Medical in the laboratory of George Palade, where he worked on the role of caveolae/lipid rafts and fenestrae in the cell biology of vascular permeability. He joined the faculty at UCSD as a Project Scientist (1999 ) and Research Assistant Professor (2000) in the Department of Cellular and Molecular Medicine continuing his studies of the molecular mechanisms of vascular permeability and the structures involved. In 2004, Dr. Stan joined the faculty of the departments of Pathology, and of Microbiology and Immunology at Dartmouth Medical School as an Assistant Professor and became Associate Professor in 2009. Currently, he is a member of the Heart and Vascular Research Center, Norris Cotton Cancer Center and affiliated with the Immunology COBRE. Since 2013 Dr Stan serves as the Director of the Optical Cell Imaging Facility and Co-Director, Irradiation, Pre-clinical Imaging and Microscopy Shared Resource, Norris Cotton Cancer Center.


Selected Publications:

 

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1-dependent and p38, JNK and PI3K/Akt-independent manner.
Hamilton BJ, Tse D, Stan RV
J Cell Mol Med. 2018 Nov 5; doi: 10.1111/jcmm.13993. Epub 2018 Nov 5.
PMID: 30394679

Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae.
Shuvaev VV, Khoshnejad M, Pulsipher KW, Kiseleva RY, Arguiri E, Cheung-Lau JC, LeFort KM, Christofidou-Solomidou M, Stan RV, Dmochowski IJ, Muzykantov VR
Biomaterials. 2018 Dec;185:348-359. doi: 10.1016/j.biomaterials.2018.09.015. Epub 2018 Sep 12.
PMID: 30273834

Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles.
Myerson JW, Braender B, Mcpherson O, Glassman PM, Kiseleva RY, Shuvaev VV, Marcos-Contreras O, Grady ME, Lee HS, Greineder CF, Stan RV, Composto RJ, Eckmann DM, Muzykantov VR
Adv Mater. 2018 Aug;30(32):e1802373. doi: 10.1002/adma.201802373. Epub 2018 Jun 28.
PMID: 29956381

Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin.
Shuvaev VV, Kiseleva RY, Arguiri E, Villa CH, Muro S, Christofidou-Solomidou M, Stan RV, Muzykantov VR
J Control Release. 2018 Feb 28;272:1-8. doi: 10.1016/j.jconrel.2017.12.025. Epub 2017 Dec 29.
PMID: 29292038

Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling.
Krispin S, Stratman AN, Melick CH, Stan RV, Malinverno M, Gleklen J, Castranova D, Dejana E, Weinstein BM
Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):353-362. doi: 10.1161/ATVBAHA.117.309571. Epub 2017 Dec 28.
PMID: 29284606

Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels.
Kenig-Kozlovsky Y, Scott RP, Onay T, Carota IA, Thomson BR, Gil HJ, Ramirez V, Yamaguchi S, Tanna CE, Heinen S, Wu C, Stan RV, Klein JD, Sands JM, Oliver G, Quaggin SE
J Am Soc Nephrol. 2018 Apr;29(4):1097-1107. doi: 10.1681/ASN.2017090962. Epub 2017 Dec 13.
PMID: 29237738

INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division.
Chakrabarti R, Ji WK, Stan RV, de Juan Sanz J, Ryan TA, Higgs HN
J Cell Biol. 2018 Jan 2;217(1):251-268. doi: 10.1083/jcb.201709111. Epub 2017 Nov 15.
PMID: 29142021

HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis.
Smits NC, Kobayashi T, Srivastava PK, Skopelja S, Ivy JA, Elwood DJ, Stan RV, Tsongalis GJ, Sellke FW, Gross PL, Cole MD, DeVries JT, Kaplan AV, Robb JF, Williams SM, Shworak NW
Matrix Biol. 2017 Nov;63:69-90. doi: 10.1016/j.matbio.2017.01.003. Epub 2017 Jan 23.
PMID: 28126521

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland.
Scully KM, Skowronska-Krawczyk D, Krawczyk M, Merkurjev D, Taylor H, Livolsi A, Tollkuhn J, Stan RV, Rosenfeld MG
Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13408-13413. Epub 2016 Nov 3.
PMID: 27810956

Endothelial Plasmalemma Vesicle-Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells.
Elgueta R, Tse D, Deharvengt SJ, Luciano MR, Carriere C, Noelle RJ, Stan RV
J Immunol. 2016 Nov 15;197(10):3970-3981. Epub 2016 Oct 14.
PMID: 27742829