Research Report 2010 - MDC

Structure of the GroupGroup LeaderFriedrich C. LuftMouse physiologyVolkmar GrossGene labSylvia BähringEicosanoid metabolismWolf-Hagen SchunckFriedrich C. LuftHypertension, Vascular Disease,Genetics, and NephrologyThe Department of Nephrology/Hypertension/Clinical Pharmacology, headed by Friedrich C.Luft (since 1992) encompassed numerous groups that are now represented independentlyelsewhere (Clinical Research Center, Ralph Kettritz, Dominik N. Müller, Maik Gollasch, KaiSchmidt-Ott). The core group has focused on genetic rearrangements as a cause of somaticalterations and cardiovascular disease. The group has also directed its attention to elucidatingmechanisms of hypertension by means of novel mouse models. In addition, the group has alsofocused on alternative mechanisms of mineralocorticoid-induced vasculopathy. The group haselucidated the role of eicosanoids in arrhythmia generation and gap junction protein function.Finally, the group has collaborated in efforts directed at salt-sensitive hypertension and noveldriving forces.Molecular geneticsSylvia Bähring leads “gene lab” a laboratory dedicated toclarifying complex genetic issues. She is not focusing onstraight-forward mutations. The primary projectinvolves autosomal-dominant hypertension withbrachydactyly type E (BDE). We now know that these(we have 5 families) are complex rearrangement syndromeson Chromosome 12p. The inversion region forhypertension and brachydactyly on chromosome 12pfeatures multiple splicing and noncoding RNA. We havesuccessfully dissected the disease-carrying chromosomalbands on the short arm of 12p with help from collaboratorsin Jena, and will now subject this material to”next-generation” sequencing. Atakan Aydin is focusingon this important issue supported by the groups of WeiChen and Norbert Hübner at the Genome Center. Weshowed earlier that our primary suspect (a gene withno open reading frames or Kozac sequences) codes for amicroRNA that is responsible for the syndrome. We areexpending most of our energies to elucidate this importantproject. Our efforts include a collaboration withMatthias Selbach and Nikolaus Rajewsky to express ourputative microRNA in HELA cells in order to find out thetarget genes on RNA and protein level and to elucidatethe functional pathways leading to the phenotypes.Philipp Maass pursues another important project of ourgroup. We studied a family BDE, albeit without hypertension.We found a t(8;12)(q13;p11.2) translocation withbreakpoints upstream of PTHLH on chromosome 12p11.2and disrupted KCNB2 on 8q13. The PTHLH translatedPTHrP protein regulates chondrocyte differentiation viaa negative-feedback loop implicating the signaling factorIHH. We determined a PTHLH down- and IHH upregulationin chondrogenic induced fibroblasts fromaffected BDE patients. We sequenced the translocationbreakpoints and found a conserved AP1 transcriptionfactor binding site on chromosome 12p11.2 and an ETS1binding site from 8q13, which resides near the AP1 sitedue to the translocation. We observed binding of bothtranscription factors at the breakpoint sequence. SinceAP1 and ETS1 interact, we tested if these factors regulatePTHLH in murine and human chondrocyte cell lines.Furthermore chondrocytes and BDE fibroblasts showeddifferent epigenetic modifications between the wildtypeand breakpoint allele with an enrichment of histonemodifications H3K4me1 and H3K4m3, which are32 Cardiovascular and Metabolic Disease Research