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Renal angiogenesis in development and disease states: Role of Eph receptors and ephrins

English title Renal angiogenesis in development and disease states: Role of Eph receptors and ephrins
Applicant Huynh-Do Uyen
Number 118369
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Embryology, Developmental Biology
Start/End 01.01.2008 - 31.12.2010
Approved amount 260'000.00
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All Disciplines (3)

Discipline
Embryology, Developmental Biology
Pathophysiology
Immunology, Immunopathology

Keywords (5)

Eph receptors; hypoxia; intussusceptive angiogenesis; intrauterine growth retardation; Thy 1.1 nephritis

Lay Summary (English)

Lead
Lay summary
BACKGROUND. Angiogenesis - the formation of new blood vessels - is a characteristic component of inflammation and is pathological in many chronic inflammatory diseases. Moreover several acute and chronic renal diseases were found recently to be associated with angiogenesis, and there is an emerging concept that manipulation of this response can attenuate the disease process.
Acute inflammation of the renal glomeruli or glomerulonephritis (GN) is a particular example of an acute inflammation. In recent years progress has been made in the understanding of glomerular injury, however little is known about mechanisms by which glomeruli spontaneously recover from injury.
Intussusceptive vascular remodeling has emerged recently as an alternative to classical sprouting angiogenesis. Intussusception modifies the branching geometry of supplying vessels, thus optimizing blood flow properties. However the relevance of intussusceptive angiogenesis in non-developmental settings and the involved molecular players remain to be investigated.

Our main research HYPOTHESES are:
a)Intussusceptive angiogenesis plays an important role in glomerular repair during acute GN.
b)Based on their involvement in cell-cell contact, EphB receptor tyrosine kinases and their ligands (ephrinB’s) seem to be the molecular players par excellence in this process.
c)Since acute GN often recapitulates important steps in glomerulogenesis (formation of new glomeruli in the embryo), we anticipate that the interplay between sprouting and intussusception is central to mammalian glomerular formation.

METHODS. We will use two complementary approaches:
1) We will use the rat Thy1.1 nephritis model - a model of acute, self limiting GN - to assess the role of Ephs/ephrins in intussusceptive angiogenesis during capillary repair
2) Concomittantly we will analyse the occurrence of intussusceptive remodeling and the spatiotemporal pattern of Ephs/ephrins during glomerulogenesis in normal pregnancy compared to hypoxia-induced intrauterine growth restriction.

RELEVANCE. The project addresses a fundamental process during inflammation, i.e. angiogenesis and capillary repair. Endothelial cell reassembly into a new network during that critical phase is a double-faced Janus. After destruction of the microvasculature by acute inflammation, adequate angiogenic remodeling could initiate the recovery of the damaged tissues. On the other hand uncontrolled, dysregulated repair could lead to scarring lesions. The identification of potential regulatory mechanisms for inflammation-associated angiogenesis could therefore provide a complementary approach to the treatment of acute inflammatory diseases.
There is growing evidence that angiogenesis is a most important concept for our understanding of renal diseases, and that manipulation of the response will have major consequences for future therapeutics. In addition, by dissecting the mechanisms governing intussusceptive angiogenesis during mammalian kidney development and acute inflammation, the project opens a new field of investigation, which will be relevant for both developmental biologists and angiogenesis researchers.

Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
105871 Eph receptors and ephrins in angiogenesis: Regulation through hypoxia 01.10.2004 Project funding

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