Activities
Without restrictions regarding the specific medical area or indication, each scientific innovation with the potential of translation from basic research to clinical application is being supported. Currently, TüCAD2 supports projects in oncology, infectious diseases, regenerative medicine and cardiovascular diseases. High quality projects are highlighted and made visible to potential external collaborators.
In addition, TüCAD2 offers coaching and consultancy in terms of academic drug discovery, project setup, validation, development plans and project management through internal resources and external networks of experts.
Another key asset is TüKIC, the Tübingen Kinase Inhibitor Collection, a >8.000 compound proprietary library of fully characterized kinase inhibitors with more than 1 Mio. data sets.
The platform focuses various regional expertises. Thus there is a close collaboration between the University of Tübingen, the University Hospital of Tübingen, the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP) Stuttgart and the Natural and Medical Sciences Institute (NMI) Reutlingen.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Oncology
RNA interference (RNAi) technology is a powerful tool and a non-biased approach for identifying genes whose suppression affects cell proliferation and viability. Although genome-wide RNAi screens have been widely used to identify new therapeutic targets in cancer, these screens are technically challenging and error-prone because of the high complexity of the short-hairpin RNA (shRNA) libraries. Using this conceptual approach, a series of relevant tumor suppressors have been identified which led to new therapeutic concepts for the treatment of various cancers, e.g. acute myeloid leukemia (AML), hepatocellular carcinomas (HCC), lung and pancreatic cancer.
The Medical Hospital in Tübingen harbors one of the very few facilities in the world with an established in vivo RNAi screening platform. Employing this technique, the molecular mechanism which leads to the development of resistance against Nexavar® (sorafenib) was discovered. Also, the activity of a protein kinase was identified as a molecular target and identified as being responsible for the resistance. Subsequently in collaboration with the Dept. of Pharmaceutical Chemistry, a drug substance which blocks kinase activity was discovered and, after testing in non-clinical safety studies, was successfully applied in patients with Sorafenib-resistant Hepatocellular Carcinoma. This example demonstrates our capacity for bench-to-bedside development of a new therapeutic concept, as illustrated in the scheme below.
Infectious Diseases
Over the last decade a new challenge has appeared in the scientific and medical community with the emergence and rapid spread of antibiotic resistance. An important limiting factor for the development of new antibiotics is that most pharmaceutical companies became reluctant to invest in this therapeutic area, because return on investment was lower than for chronic diseases. As a consequence, research programs for novel antibiotics are currently being primarily carried out by biotech companies and academic consortia, supported by public funding and public/private partnerships.
Within the NatResource Center of the University of Tübingen, scientists of the Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), the Dept. of Organic Chemistry, and the Dept. of Pharmaceutical Biology jointly collaborate towards the identification and characterization of new antibiotics with new modes of action and resistance-breaking capabilities. The University and the University Hospital Tübingen are member of the German Center for Infection Research (DZIF) which supports these translational efforts.
Regenerative Medicine
The definitive treatment option for acute liver failure and end-stage chronic liver failure is transplantation. However, the number of available donor livers is limited. Despite liver cells having a great capacity to proliferate under physiological conditions, regeneration defects are often encountered in chronic liver diseases. The regeneration therefore is insufficient to compensate the loss of hepatocytes and organ function.
Following a functional genetic approach for the identification of gene targets can be exploited to increase the regenerative capacity of hepatocytes. Pools of small hairpin RNAs (shRNAs) were directly and stably delivered into mouse livers to screen for genes modulating liver regeneration. These studies identified Mitogen-activated protein kinase MKK4 as a major regulator of liver regeneration by a faster cell-cycle entry and progression of hepatocytes. On the other hand, in settings of acute and chronic liver damage MKK4 induces an increased regenerative capacity of hepatocytes. The development of small molecular MKK4 inhibitors may therefore represent a novel therapeutic strategy for the treatment of patients with acute or chronic liver disease.
Cardiovascular Diseases
Blood platelets are small cells without nuclei that play a critical role in preventing excessive bleeding at sites of injury, a process known as hemostasis. However, platelet activation also triggers blood clotting within damaged blood vessels (thrombosis), which can cause heart attacks and strokes, two of the leading causes of death and severe disability worldwide. A deepened understanding of the role of platelets in cardio- and cerebrovascular diseases has led to significant improvements in, but often at the expense of bleeding complications. In addition, recent evidence has suggested that platelets perform further roles beyond thrombosis and hemostasis. However, the molecular mechanisms and therapeutic relevance of these novel platelet functions are largely unknown.
We explore the roles of platelet CXCL-chemokines and CXC-receptors on thrombo-inflammation following organ ischemia (heart and brain). The project aims to develop novel therapeutic strategies for ischemic organ dysfunction to overcome currently limited treatment options.