ENDomics Lab (Endothelial Research Group)
Location:
University Medical Center Hamburg-Eppendorf
Department of Oncology, Haematology and Bone Marrow Transplantation
Campus Forschung (N27), Ground Floor, Rm 00.073/ 00.074/ 00.100
Martinistr. 52
20246 Hamburg
Phone:
Fax:
+49 40 7410-57187 (Laboratory)
+49 40 7410-40084 (Office)
Website (external link):
http://www.endomics.de
Core Team Members:
Dr. rer. nat. Jakob Körbelin (PI)
Dr. med. Jan K. Hennigs (PI)
Maria Stamataki, M.Sc. (Ph.D. student)
Merrit Rothe, M.Sc. (Ph.D. student)
Julia Lüschow, MSc (BTA, Lab manager)
Zexin Cao, Master of Surgery (Dr. med. candidate)
Julius Klein (Dr. med. candidate)
Overview:
Endothelial dysfunction is hallmark of vascular diseases and cancer. We, therefore, apply an integrative multi-omics approach supplemented by in silico-based bioinformatics and functional cell biology to decipher the pathological molecular signatures of endothelial cells in different vascular diseases and lung cancer. By developing organo-specific AAV vectors specifically-targeting endothelial cells we are able to study the molecular basis of endothelial dysfunction and evaluate the potential of new endothelium-based pharmacological and gene therapies.
Main focus
Vascular gene therapy
Principle Investigator: Dr. rer. nat. Jakob Körbelin
Background:
As a kind of giant networked organ, the vasculature is an essential part of the human body that supplies every single cell in the body with oxygen and nutrients. The blood vessels of a single person extend over a total length of around 100,000 km, which corresponds to a distance of 2.5 circumnavigations of the earth. The capillaries, which consist of only one layer of endothelial cells (EC), are the smallest blood vessels in the body and account for around 80% of the total vascular distance. It is therefore not surprising that a large number of diseases can be traced back to endothelial dysfunction. Our team is working on the development of novel endothelial gene therapy approaches for a wide range of diseases that are associated with vascular dysfunction, even beyond typical pulmonary and cardiovascular diseases.
Technology:
Viral vectors based on the adeno-associated virus (AAV) are extremely promising vehicles for introducing genes into human cells. Various such AAV vectors ("gene shuttles") have already been successfully used in preclinical and clinical studies for the gene therapy of a wide range of diseases. For some initial indications, AAV vectors have already been approved by the regulatory authorities in the EU and the USA for treatment by means of gene therapy. Unfortunately, most of the available AAV vectors cannot be used efficiently for gene transfer into endothelial cells. To redirect AAV particles to new, previously inaccessible targets (here: endothelial cells or endothelial surface molecules), we use randomized peptide banks, which are presented on the capsid surface of AAV particles. These randomized AAV peptide banks, developed in the Receptor Targeting Laboratory of Prof. Martin Trepel, contain up to about 100 million different peptide presenting AAV capsid variants. Using in vivo screening approaches over several rounds of selection, we have succeeded in isolating endothelial AAV vectors with specificity for different organs such as the brain (AAV-BR1) or the lung (AAV2-ESGHGYF). The use of these AAV vectors already enables us to preclinically evaluate novel gene therapy approaches for neurological and penumological diseases (see section: Molecular pathogenesis of vascular lung diseases). In addition, we are continuously working on optimizing our randomized AAV peptide banks and our selection approaches (in vitro, in vivo, ex vivo and combinations) to isolate optimized AAV vectors. In this way, we aim to increase vector efficacy and expand the spectrum of existing AAV vectors to include additional organs and organisms.
Main focus
Molecular pathogenesis of vascular lung diseases
Principle Investigator: Dr. med. Jan K. Hennigs
Background:
All vascular diseases including pulmonary vascular diseases are characterized by pathological, vascular structural changes (so-called "remodelling").
The relatively rare disease of pulmonary arterial hypertension (PAH) serves us as a model disease for pulmonary vascular diseases, as it is characterized by initial loss of microvessels due to increased endothelial cell apoptosis in combination with the formation of a neointima and medial and adventitial thickening due to uncontrolled growth of fibroblasts and smooth muscle cell-like cells.
This pathological vascular remodeling, which also occurs in a very similar form in vessels of patients with bronchial carcinomas, is closely associated with (epi)genetic changes due to pathologically disturbed signal transduction to the transcription factor p53. However, in lung endothelium, activation and stabilization of p53 is essential for the maintenance of mitochondrial structure and function, genomic DNA integrity, angiogenic and regenerative potential and endothelial cell survival under oxidative or genotoxic stress conditions.
However, the exact transcriptional landscape (and their interactions) for maintaining endothelial survival, DNA and vascular integrity in the lung remain unclear despite intensive research efforts.
Deciphering the epigenetic and transcriptional-regulatory mechanisms in the lung vasculature may therefore help to develop novel vasoregenerative therapeutic strategies that reverse pathological vascular remodeling.
Technology:
We use systems biology methods coupled with genetic and functional cell biology approaches to further decipher the molecular pathogenesis of predominantly pulmonary vascular diseases.
For this purpose, samples from our newly established departmental endothelial cell biobank are available for analysis using protein biochemical, cell biological and systems biology technologies from the fields of proteomics (AP-MS), epigenomics, transcriptomics as well as data mining in publicly available datasets for integrative in silico omics analyses and drug repurposing paired with AAV-based, organ-specific, genetic in vivo tools (see section: Vascular Gene Therapy).
Aims:
- Identification of pathophysiologically relevant epigenomic and transcriptional regulatory mechanisms in pulmonary vessels
- Characterization of their biological function and significance in endothelial primary cell cultures from healthy donors and patients with pulmonary vascular diseases and bronchial carcinomas
- Determination of their (gene) therapeutic potential with regard to pulmonary vascular regeneration and repair.
Publications:
An overview of current publications by members of the working group can be found at Pubmed .