ENDomics Lab
Endothelial Dysfunction Research Group
Group Leaders: Jan K. Hennigs (MD, DMsc) & Jakob Körbelin (PhD)
Head of Division: Hans Klose (MD, PhD)
Division of Pneumology
Department of Oncology, Haematology and Bone Marrow Transplantation
Campus Forschung (N27), Ground Floor, Rm 00.073/ 00.074/ 00.100
University Medical Center Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Telephone:
+49 40 7410-59719 (Lab)
+49 40 7410-58798 (Office Dr. Körbelin)
+49 40 7410-51980 (Office Dr. Hennigs)
Telefax:
+49 40 7410-57187 (Lab)
+49 40 7410-40084 (Office)
Website (external):
Core Team Members:
Dr. med. Jan K. Hennigs (PI)
Dr. rer. nat. Jakob Körbelin (PI)
Dr. rer. nat. Christiane Matuszcak (Postdoc)
Susanne Ghandili, MD (Scientist)
Julia Mienert, MSc (BTA, Lab Manager)
Joelle Korte (Medical Student)
Johannes Runge (Medical Student)
Flemming Meyer (Medical Student)
Overview:
Endothelial dysfunction is hallmark of vascular diseases and cancer. Pulmonary vascular diseases (PVD) and pulmonary arterial hypertension (PAH) in particular are vasoproliferative conditions characterized by severe endothelial dysfunction in the lung and beyond. Available pharmacotherapeutic approaches are only able to slow down disease progression and lung transplantation often remains the only treatment option in advanced disease. 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 pulmonary 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.
The background and technologies of our lab’s two core areas are briefly introduced below.
Molecular Pathogenesis of Endothelial Dysfunction in the Lung
Focus Lead: Dr. med. Jan K. Hennigs (MD)
Mission and Background:
Pulmonary vascular diseases (PVD), and pulmonary arterial (PA) hypertension (PAH) in particular, are life-threatening diseases. These conditions are characterized by pathological structural changes to the lung vessels called remodeling. Lung vessel "remodeling" is associated with progressive narrowing of the vessel lumen and loss of precapillary vessels causing increasing pulmonary vascular resistance, pulmonary artery pressure and consecutive right heart failure. Moreover, pulmonary vascular remodeling is also found in hypoxic lung diseases and lung cancer where it substantially contributes to disease related mortality.
PAH serves as our model diseases as it is characterized by initial microvessel loss through aberrant endothelial cell apoptosis in conjunction with neointima formation and adventital thickening by uncontrolled proliferation of smooth muscle (like) cells and fibroblasts.
Medical Need:
All currently approved PAH therapies mainly focus on dilating the structurally abnormal vessels and but do not decisively reverse vascular remodeling.
Pathological remodeling of the pulmonary vasculature is closely related to (epi)genetic changes mediated by dysfunction of canonical and non-canonical Bone Morphogenetic Protein Type 2 Receptor (BMPR2) signaling via downstream transcription factors (TFs) . BMPR2 is dysfunctional in the PA of the majority of PAH patients, whether familial, idiopathic or associated with a variety of underlying medical conditions (APAH).
In healthy PA and lung microvascular endothelial cells (ECs) activation of non-canonical TF complexes downstream of BMPR2 is important to maintain mitochondrial structure and function, DNA integrity, angiogenetic plasticity, recovery from genotoxic & oxidative stress and lastly maintain EC survival in order to prevent pathological vascular remodeling.
In the pulmonary vasculature, the transcriptional landscape (as well as its interdependency) facilitating EC survival, maintaining DNA and vessel integrity is incompletely understood. Elucidation of the epigenetic and transcriptional regulatory mechanisms could help identify novel vasculoregenerative strategies to reverse detrimental pathological PA remodeling found in the lungs of transplanted PAH patients.
Technology:
We use systems biology methods as well as genetic and functional approaches to study the molecular pathogenesis of pulmonary vascular diseases. By utilizing affinity purification and plasma proteomics, whole-genome epigenomics, transcriptomics, public data mining, in silico co-occupation studies, immunohistochemistry, organo-specific genetic in vivo tools (lung EC-specific AAV), as well as molecular and functional cell biology methodologies, we aim
- to identify novel important epigenomic and transcriptional mechanisms in the pulmonary vasculature.
- to determine their biological function in healthy and diseased primary cells and tissues from patients with pulmonary (vascular) diseases
- to characterize their druggability (drug repurposing) and (gene-)therapeutic potential.
- to validate novel disease modifying therapeutic, vasculoregenerative approaches in models of PAH, lung cancer and cardiovascular disease.
Vascular Gene Therapy
Focus Lead: Jakob Körbelin (PhD)
Mission and Background:
The vasculature is an essential part of the human body and provides every single cell in each organ with nutrients and oxygen. The blood vessels of one single person stretch over a total length of 100,000 km which equals the distance of 2.5 times around the globe. Capillaries consisting of only one layer of endothelial cells are the smallest vessels in the body and account for 80% of the total vessel length. Endothelial cells play a pivotal role in regulating the integrity of the whole vascular system. A healthy and intact vasculature in turn is essential for keeping up the body’s fine-tuned homeostasis. It is not surprising that a vast number of diseases is linked to endothelial dysfunction. We believe that endothelial cells are the key to treating a broad range of diseases, especially those affecting the well-perfused large organs such as lung and brain. Moreover, malignant diseases may be treated by targeting endothelial cells, as tumor development and metastasis are heavily influenced by the tumor vasculature. Our team is working on the development of novel endothelial-based gene therapy strategies for a broad range of diseases linked to vascular dysfunction. As part of the ENDomics lab, we are most strongly interested in (but not limited to) pulmonary diseases with a focus on pulmonary (arterial) hypertension.
Technology:
Viral vectors based on the adeno-associated virus (AAV) are a very promising tool to deliver therapeutic genes to human cells. Different AAV vectors have successfully been used in preclinical and clinical gene therapy trials for a broad range of diseases and some of them have even been approved for commercial gene therapy in the USA and the EU. Unfortunately, most available AAV vectors lack efficient tropism for endothelial cells. To re-direct AAV to new, formerly inaccessible targets (i.e. endothelial cells) we employ random peptide libraries displayed on the AAV capsid. Our AAV display peptide libraries, which have initially been developed in Martin Trepel’s Receptor Targeting Lab, consist of up to 100 million different peptide-presenting capsid variants. By employing in vivo screening approaches over multiple selection rounds on the target cells of choice, we have been able to isolate endothelial-directed AAV vectors for different organs such as AAV-BR1 (brain ECs) and AAV2-ESGHGYF (pulmonary ECs). Employing these vectors, we are able to assess novel gene therapy approaches of brain and lung diseases in preclinical settings. In addition, by constantly improving our screening approaches (in vitro, in vivo, ex vivo and combinations thereof) and by constantly improving our random AAV display peptide libaries, we aim to further increase vector efficacy and expanding our portfolio of targeted AAV vectors to different organs and species.
Publications:
Find our lab member's complete list of publications at
Pubmed
.
Interested in joining us?
We are constantly looking for highly motivated medical or master’s students.
Feel free to contact us by email
Dr. Jakob Körbekin ( j.koerbelin@uke.de )
Dr. Jan K. Hennigs ( j.hennigs@uke.de )