Patientenkolloquium 2019
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Project TP03

PD Dr. rer. nat. Arne Schäfer
Institute of Clinical Molecular Biology and 1st Department of Internal Medicine
University Hospital Schleswig-Holstein

Prof. Dr. Dr. Søren Jepsen, M.S.
Department of Periodontology, Operative and Preventive Dentistry
Center of Dento- Maxillo- Facial Medicine
Medical Faculty
University of Bonn

Prof. Dr. Stefan Schreiber
Institute of Clinical Molecular Biology and 1st Department of Internal Medicine
University Hospital Schleswig-Holstein

First Funding Period

Genetic Investigation of Pathophysiological Relevant Processes in Periodontitis

The epidemiology of periodontitis is consistent with the multifactorial aetiology of complex diseases in which for the majority of cases the disease development depends on the collective presence of environmental risk factors (e.g. smoking, oral hygiene, etc.) in conjunction with various genetic risk factors. Here, we propose a strategy in which the detailed knowledge of disease pathophysiology in periodontitis within the research group will be used to guide a comprehensive genetic exploration of the etiological relevance of these genes. We will cover key disease genes in pathophysiology by a haplotype tagging approach using the SNPlex? and TaqMan? technology (Hampe, 2001).

We will investigate Aggressive Periodontitis (AgP) as an extreme phenotype in which we expect a higher degree of genetic contribution due to its early onset and rapid development. The phenotype definition requires diagnosis before the age of 35 and a rapid bone loss and subsequent tooth loss documented by X-ray radiographs. The AgP subform of periodontitis is a comparatively rare disease with a prevalence of 0.1% - 0.2% (Hansen B.F. et al., 1984; Kronauer et al., 1986; Sacby M., 1984). In addition, we employ a well defined clinical exploration sample of Chronic Periodontitis (CP), the less severe but most common type, for further exploration and verification of eventual association findings in AgP.


Second Funding Period

Functional characterization of the long antisense noncoding RNA CDKN2BAS (ANRIL) and elucidation of the specific role in the pathophysiology of periodontitis

Genetic exploration of potential key disease genes of periodontitis allowed us the identification of the first shared genetic risk gene of periodontitis and coronary heart disease (CHD), termed ANRIL (CDKN2BAS). The biological function of ANRIL is currently largely unknown. In previous works we identified different regulation of alternatively spliced ANRIL transcripts in gingival fibroblasts upon stimulation with pathogenic bacteria in relation to the specific genetic background. These transcripts may have distinct physiological and tissue specific functions, and changes in the splicing patterns potentially have pathological relevant effects. We will address the following questions: (1) Minute elucidation of differently regulated splicing variants of ANRIL within gingival fibroblasts (hGF) and arterial endothelial cells. (2) Identification of the nuclear localisation of the two main ANRIL transcripts by FISH. (3) Identification of putative protein binding partners of the major tissue specific ANRIL transcripts. (4) Genome-wide expression profiling upon inducible over-expression and knockdown of ANRIL in gingival fibroblastic cells of homozygous background for the disease associated as well as the common alleles to elucidate the transcriptional regulatory effects of ANRIL on a genome-wide level. (5) Targeted re-sequencing of the genomic region of ANRIL in patients who are homozygous for the two main associated haplotype blocks to identify the functional genetic variants. We will subsequently test these variants for their etiological relevance in CHD.