The anatomic location of the endothelial cell makes it an ideal target for in vivo gene transfer with consequent genetic modification of the endothelial cell for a variety of therapeutic purposes, including induction of angiogenesis, prevention of restenosis, following angioplasty, suppression of vessel growth in tumors, and as a source of therapeutic proteins for treatment of hereditary and acquired disorders. Of all gene transfer vectors available, adenovirus has been most effective at mediating endothelial gene transfer, but high vector concentrations are necessary, with the attendant risks for adverse events related to the vector. In this context, strategies using adenovirus vectors to transfer genes to endothelial cells could benefit from improved efficiency of gene transfer to endothelial cells which would lead to a corresponding decrease in dose of vector delivered to the patient. To realize the potential for increasing gene transfer to endothelial cells, the biology of gene transfer to endothelial cells must first by characterized. In this context, the central hypothesis of this proposal is that the evaluation of adenovirus trafficking in endothelial cells will yield strategies for improved efficiency of gene transfer to endothelial cells. To pursue this hypothesis, adenovirus interaction with endothelial cells will be evaluated in the context of varying physiological states of endothelial cells including resting or activated endothelial cells, as sub-confluent cultures, confluent polarized monolayers, or wounded polarized monolayers. These strategies will lay a foundation for understanding the impact of altered adenovirus tropism on efficiency of gene transfer to endothelial cells. This project is focused on two aims: (1) To characterize efficiency of adenovirus binding and intracellular trafficking in varying physiological states of endothelial cells; and (2) To characterize adenovirus entry and trafficking in endothelial cells subsequent to infection via alternate cell surface receptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL059312-07
Application #
7575009
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
7
Fiscal Year
2003
Total Cost
$290,389
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Ding, Bi-Sen; Nolan, Daniel J; Butler, Jason M et al. (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468:310-5
Kobayashi, Hideki; Butler, Jason M; O'Donnell, Rebekah et al. (2010) Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12:1046-56
Rabbany, Sina Y; James, Daylon; Rafii, Shahin (2010) New dimensions in vascular engineering: opportunities for cancer biology. Tissue Eng Part A 16:2157-9
Rafii, Shahin; Nolan, Daniel (2010) Cholesterol activates vascular niche and hematopoiesis. Blood 115:3857-8
Yamamoto, Masaya; James, Daylon; Li, Hui et al. (2010) Generation of stable co-cultures of vascular cells in a honeycomb alginate scaffold. Tissue Eng Part A 16:299-308
Butler, Jason M; Kobayashi, Hideki; Rafii, Shahin (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10:138-46
Butler, Jason M; Nolan, Daniel J; Vertes, Eva L et al. (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6:251-64
James, Daylon; Nam, Hyung-song; Seandel, Marco et al. (2010) Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol 28:161-6
Kiuru, Maija; Hidaka, Chisa; Hubner, Ralf-Harto et al. (2009) Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment. Mol Ther 17:1442-52
Hooper, Andrea T; Shmelkov, Sergey V; Gupta, Sunny et al. (2009) Angiomodulin is a specific marker of vasculature and regulates vascular endothelial growth factor-A-dependent neoangiogenesis. Circ Res 105:201-8

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