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mTORC1 and mTORC2 as potential molecular targets for therapeutic angiogenesis

English title mTORC1 and mTORC2 as potential molecular targets for therapeutic angiogenesis
Applicant Battegay Edouard
Number 118349
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Allgemeine Innere Medizin Medizinische Universitätsklinik A Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Cellular Biology, Cytology
Start/End 01.01.2008 - 31.10.2012
Approved amount 296'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Cardiovascular Research

Keywords (6)

therapeutic angiogenesis; signaling; mTORC1; mTORC2; VEGF; bradykinin

Lay Summary (English)

Lead
Lay summary
Several diseases, such as ischemic heart disease, are the result of failure or insufficient blood vessel formation and supply. Therapeutic angiogenesis is a novel experimental treatment that may inhibit or induce the creation of new blood vessels in the body of patients in order to combat these diseases. Bringing new nutrients and oxygen to the damaged site by a local expansion of blood vessels may thus facilitate repair and function. However, controlling new micro blood vessel formation has proven to be difficult. Treatment with single compounds often resulted in the formation of aberrant, non-functional blood vessels. Gradients, concentrations and combinations of active compounds, local oxygen content and tissue composition all influence the development of newly emerging micro vessels. Ideally, a common circuit, through which all these signals would act and that controls angiogenesis would be the target of choice.With this research proposal we want to examine a central and strongly interlaced circuit inside of blood vessel cells that is known to control growth. We assume that it steers the strength of blood vessel-stimulating signals by means of two different functional units, namely mTORC1 and mTORC2. We reason that mTORC1 determines, whether a blood vessel will grow, and mTORC2 is responsible for vessel architecture and functionality. We will switch of the function of these units in blood vessel cells in genetically modified mice, stimulate angiogenesis with gradients of active compounds and then analyze blood vessel abundance and architecture. The research will be complemented with studies and assays in cells and in blood vessel growth in culture.The mTORC units were discovered only recently and little is known about the function of mTORC2 in particular. Our results will determine whether the mTORC units may be targeted in future for pro- or anti blood vessel therapy, an asset interesting for pharmaceutical companies that develop drugs for therapeutic angiogenesis. The research will also increase our understanding of how blood vessels develop and how active compounds can be used to safely grow blood vessels in patients in current clinical trials.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation.
Walpen Thomas, Kalus Ina, Schwaller Jürg, Peier Martin A, Battegay Edouard J, Humar Rok (2012), Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation., in Biochemical and biophysical research communications, 429(1-2), 24-30.
Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells.
Walpen Thomas, Peier Martin, Haas Elvira, Kalus Ina, Schwaller Jürg, Battegay Edouard, Humar Rok (2012), Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells., in Cellular physiology and biochemistry : international journal of experimental cellular physiology, bi, 30(4), 1083-1096.
Sprouty2 expression controls endothelial monolayer integrity and quiescence.
Peier Martin, Walpen Thomas, Christofori Gerhard, Battegay Edouard, Humar Rok, Sprouty2 expression controls endothelial monolayer integrity and quiescence., in Angiogenesis.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael Hall, Biozentrum Basel, Department of Biochemistry, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. J. Schwaller, Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Luisa Iruela-Arispe, Department of Molecular, Cell & Developmental Biology, UCLA, Los Angeles United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. G. Christofori, Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. N. Lindenblatt, Division of Plastic and Reconstructive Surgery, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

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