|Title / Titel||Metzincin and Extracellular Matrix Protein Expression Profiles in Patients with IgA Nephropathy and Chronic Renal Allograft Rejection as Markers for Disease Mechanisms, Prognosis and Therapeutic Targets|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||Hypothesis:
· In IgA nephropathy and in chronic renal allograft rejection, alterations in the expression of metzincins, of their substrates and of their regulating factors show a correlation with glomerular and tubulointerstitial damage.
· The altered expression patterns of these genes help to elucidate pathogenetic mechanisms, to predict disease progression and to adjust medical therapy.
· Interventions targeted at modifying activity and expression of metzincins, for instance by MMP inhibitors, antisense oligonucleotides or small interfering RNA (siRNA), or of their substrates and regulating factors ameliorate experimental renal damage.
Strategy and Methods
In part 1, we will analyze the expression profile of metzincins and related factors (e.g. matrix proteins, cytokines) in kidney biopsies using AffymetrixÒ HG-U133A microarrays. Thereby, we investigate patients with renal allograft dysfunction (mainly chronic rejection) and with IgA nephropathy. The studies involving IgA nephropathy will be performed in collaboration with the European Renal cDNA Bank (ERCB) and will be extended with custom made microarrays for the investigation of a much larger patient group. The respective analyses of patients with renal allograft biopsies are already about to be completed.
In part 2, we will confirm microarray data by real-time PCR and immunohistochemistry. Thereafter, gene expression data will be correlated with histological and clinical parameters. For these studies, we will utilize RNA left over from microarray analyses and biopsy material from our institution.
Finally, in part 3, we plan to perform interventional studies in experimental mesangial proliferative glomerulonephritis (anti-Thy1.1 nephritis), already introduced in our laboratory. Interventions may consist in the application of synthetic protease inhibitors, antisense oligonucleotides or siRNA targeted at metzincins, their substrates (e.g. matrix proteins) or their regulators. Their application may occur systemically or by directed drug delivery to mesangial cells using immunoliposomes, as developed by us.
|Publications / Publikationen||Lods N, Ferrari P, Frey FJ, Kappeler A, Berthier C, Vogt B, Marti HP: Angiotensin-converting enzyme inhibition but not angiotensin II receptor blockade regulates matrix metalloproteinase activity in patients with glomerulonephritis. J Am Soc Nephrol, 14(11):2861-2872, 2003.Berthier C, Lods N, Joosten SA, van Kooten C, Leppert D, Lindberg RLP, Kappeler A, Raulf F, Sterchi EE, Lottaz D, Marti HP: Differential regulation of metzincins in experimental renal allograft rejection: potential markers and novel therapeutic targets. In revision.|
|Keywords / Suchbegriffe||glomerulonephritis, microarray, immunoliposomes, chronic renal allograft rejection|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|SNF (Personen- und Projektförderung)
|In collaboration with /
In Zusammenarbeit mit
|Duration of Project / Projektdauer||Jan 2004 to Jan 2008|