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Group Weber - Projects
Our main reasearch goal aims to elucidate neurodegenerative mechanisms in the model system of the highly specialized mammalian retina. In previous years, major efforts were directed towards the identification of the genetic causes underlying the hereditary retinal dystrophies. Here, we were able to contribute specifically to the area of the macular dystrophies by cloning disease genes for conditions such as Sorsby fundus dystrophy (Weber et al. Nat Genet 8:352-6, 1994), X-linked juvenile retinoschisis (Sauer et al. Nat Genet 17:164-70, 1997) or Best vitelliforme macular dystrophy (Marquardt et al. Hum Mol Genet 7:1517-25, 1998). Our ongoing work focuses on investigations into the respective pathomechanisms of these diseases. Apart from a broad methodological platform in molecular genetics and biochemistry, our approaches also include cell biological techniques and the generation and analysis of mouse models of retinal degeneration.
The X-linked juvenile retinoschisis (RS) project is an example illustrating our efforts to bridge the gap between gene cloning and providing therapeutic treatment options for patients suffering from a hereditary retinopathy. We have now succeeded in providing proof-of-concept for the gene therapy treatment of RS in the retinoschisin-deficient mouse via adeno-associated virus (AAV). We have shown that a unique treatment early in postnatal development results in a rescue of photoreceptors and retinal architecture over the entire life span of the mouse (Min et al. Mol Ther 12:644-51, 2005).
For many years now we are greatly involved in the genetics of the multifactorial age-related macular degeneration, a highly prevalent threatening disease in industrialized countries. Our main interest is to identify the genetic factors predisposing to this sight-threatening disease. In particular, we apply a SNP-based platform in a case/control association study design to test plausible gene candidates (e.g. Fisher et al. Hum Mutation 28:406-413, 2007) or to identify novel loci by genome-wide scans (Rivera et al. Hum Mol Genet 14:3227-36, 2005). Similar to the monogenic diseases, AMD-associated gene variants are also functionally analyzed to further study thee mechanisms of disease pathology.
At present the following grant-supported projects are ongoing:
Project descriptions

Funktionelle und strukturelle Eigenschaften des Bestrophin-1 und dessen Rolle in der Pathogenese von Morbus Best
Morbus Best ist eine autosomal dominante Erkrankung des retinalen Pigmentepithels (RPE), die sich als typische Eidotter-ähnliche Läsion im zentralen Bereich des hinteren Augenpols manifestiert. Als Schlüsselmerkmal gilt eine elektrophysiologische Besonderheit, der sogenannte verminderte Hellanstieg im Elektrookulogramm (EOG). Ein progredienter Verlust des zentralen Visus geht mit atrophischen Veränderungen des RPE und der darüberliegenden Netzhaut einher. Ursächlich finden sich Mutationen im Bestrophin-1, einem integralen Membranprotein des RPE, dessen Funktion gegenwärtig kontrovers diskutiert wird. So könnte das Protein eine regulatorische Rolle in der Ca2+-Homöostase von RPE Zellen besitzen oder als Ca2+-abhängiger Cl--Kanal direkt die Cl--Leitfähigkeit der basolateralen RPE Membran beeinflussen. Beide Hypothesen können bislang allerdings nicht die Visus-mindernden degenerativen Prozesse dieser Erkrankung befriedigend erklären. Eine Assoziation von Bestrophin-1 Mutationen mit dem Krankheitsbild des ADVIRC einschließlich Nanophthalmos macht eine weitere Funktion des Bestrophin-1 auch in der frühen okulären Entwicklung wahrscheinlich. Ziel unserer Forschung ist es zum einen die bisher unvollständig verstandenen Funktionen von Bestrophin-1 zu charakterisieren und darüber hinaus die pathologischen Mechanismen von mutantem Bestrophin-1 zu verstehen. Hierzu stützen wir uns schwerpunktmäßig auf eine Reihe von uns etablierter Bestrophin-1 Mausmodelle, die phänotypisch, biochemisch, zellbiologisch und elektrophysiologisch umfassend charakterisiert werden. Damit soll ein Beitrag zum Verständnis der grundlegenden funktionellen Mechanismen Bestrophin-1 vermittelter Degeneration der Netzhaut geleistet und der Weg für Evidenz-basierte Therapieoptionen geebnet werden.

Functional analysis of retinoschisin A contribution to elucidate the molecular pathogenesis of X-linked juvenile retinoschisis
X-linked juvenile retinoschisis (RS), a recessively inherited retinal dystrophy, is caused by mutations in the retina-specific gene RS1 encoding retinoschisin. The functional protein is secreted as a homo-octameric complex from photoreceptors and bipolar cells and due to its evolutionarily conserved discoidin domain, is likely involved in cellular adhesion and/or signalling processes on plasma membrane surfaces. Our main objective is to elucidate the molecular mechanisms and cellular pathways associated with retinoschsisin-binding to the plasma membrane. This will be key to understanding the primary molecular events in RS pathology triggered by absent or non-functional retinoschisin. The retinoschisin-deficient mouse which was generated in our laboratory will be indispensable for the projected efforts which mainly focus on two major areas. One is aimed at defining and characterizing retinoschisin binding to the plasma membrane, the other intends to elucidate the primary and secondary molecular events associated with loss of functional retinoschisin. By applying state-of-the-art experimental designs, our ongoing work is aimed to further the molecular understanding of a retinal protein that is crucial to ensure long-term maintenance of retinal architecture.

Functional analysis of AMD-associated variants in the LOC387715/HTRA1 interval on chromosome 10q26
Age-related macular degeneration (AMD) is a complex disorder of the central retina with readily increasing socio-economic significance in industrialized countries. With a prevalence of about 12% in the population over 80 years of age, advanced forms of AMD are nowadays the most common cause of blindness in the elderly. Recent work from our and other groups has identified genetic variants in two genomic regions at 1q32 and 10q26 which independently confer high risks for developing disease pathology. At 1q32, association signals were shown to culminate over the complement factor H (CFH) gene implicating innate immunity and inflammation in the aetiology of AMD. At 10q26 strongest association is found within a region of high linkage disequilibrium (LD) harbouring the hypothetical gene LOC387715 and parts of HTRA1 (HtrA serine peptidase 1), a secreted serine protease likely regulating the degradation of extracellular matrix proteoglycans. The aim of our research is to characterize the disease-associated variants within the region of high LD in the 10q26 region and to assess their functional consequences with regard to the two candidate genes. This will allow us to gain further insight into possible pathways and mechanisms leading to AMD pathology and may provide new target molecules paving the way for novel therapeutic options to treat this devastating disease.