Cardiac Sheddomics
I. Exploring the functional relevance of Adam Metalloproteases during cardiac development and homeostasis of mice and men
Proteolytic processing of cell surface membrane proteins is also referred to as Ectodomain Shedding. Hereby, the zinc-dependent family of A Disintegrin and Metalloproteases (ADAM) represents one of the most diversely expressed and (patho-)physiologically relevant classes of Ectodomain-Shedasses. ADAM-dependent Ectodomain-Shedding was shown to be essential for embryonic cell-differentiation and cell-fate decisions among various tissues as well as homeostasis and regenerative processes in adult cells. The precise molecular function of ADAM Metalloproteases on development and homeostasis of the myocardium is however still unexplored.
Fig.1: Schematic drawing of the Ectodomain Shedding Process (aus Weber & Saftig 2012, Development)
We are currently working to close this knowledge gap by studying cardiomyocyte-restricted ADAM10 knock-out mice as well as cardiac tissues from CVD patients. First results from these studies confirm the central role of ADAM10 in CVD processes and we will now proceed to transfer this knowledge into sophisticated animal and cellular models to gain a better understanding of the underlying mechanistical principles. The ultimate goal will be translation of the experimentally received results into novel ADAM10 activity modulating pharmacological therapies.
II. ADAM Metalloproteases as pharmacological targets: „Refining status quo and looking beyond“
Numerous studies confirm the extraordinary importance of ADAM10 during (embryonic) development, tissue de- and regeneration in vitro and in vivo. On a molecular basis, this maybe primarily transduced via regulation of:
| a) | Cellular differentiation and/or proliferation via e.g. Notch/Wnt/ β-catenin signal transduction |
| b) | Intercellular adhesion via e.g. Cadherin and Ephrin-Proteolysis |
| c) | Protein aggregation via de-regulated Amyloid Precursor Protein (APP) or Prion- Protein Processing. |
Misregulation of these major signal transduction pathways will inevitably lead to pathophysiological consequences in mice and men. Thus, ADAM10 should be a promising drug target. However early lethality of constitutive and conditional ADAM10 knock-out mice as well as disappointing (pre-)clinical studies with (rather unspecific) ADAM/MMP inhibiting small molecule compounds in the 90s have dampened the enthusiasm of academic researchers and pharmaceutical industries to further evaluate ADAM(10) as drug target. Nevertheless recent studies using more ADAM(10) specific substances (inhibiting as well as activating) did not show any overt toxic effects thus re-establishing them as valuable drug targets. Based on this knowledge and in combination with novel innovative concepts we were able to win Boehringer Ingelheim and Novartis as important industrial partners to push preclinical evaluation of ADAM10 as putative drug target.
We believe that ADAM10 will become an effective starting point to combat a variety of diseases. Now WE will have to prove this hypothesis – and WE are all focussed on this goal!
Abb. 3: FRET-based screening assay to identify novel drug compounds targeting ADAM10/17 activity.
Scientific Intrapreneuring
Inventions and subsequent innovation are the major driving force in science and society. Due to their excellently trained scientific & administrative personnel, diverse infrastructure and allocated budgets, universities offer a highly suitable environment to drive such complex processes. Nevertheless, real and sustainable innovation is usually earned much more difficult in practical life. Probable reasons for this circumstance are manifold and are usually not easy to resolve. Rigid career paths, individual interests, inflexible funding modalities are just a few of them. Nevertheless, outstanding innovations are still happening in the university environment.
But how does it work?
My personal experience and observations from more than ten years as an academic scientist showed me that often persons with a special drive are capable to overcome obstacle, enter the unknown, think and act in lateral or parallel ways but are also able to gather and enlighten a powerful team around them; or with one word: Entrepreneurs! Sadly many of this persons leave the universities early to either because they do not fit well to the available promotion and reward system or in order to start their own business. As a consequence, universities and by definition also the public, to which the university actually belongs, squander this innovation potential pretty ruthlessly.
I believe that we can stop this development in case we offer novel career paths and funding modalities to entrepreneur like persons who want to stay in the academic environment (Intrapreneurs) and serve the common good. Fortunately, the director of the Integrative Center for Pharmacology and Toxicology (IZPT) Prof. Dr. Ali El-Armouche is deeply supporting my intrinsic wish and enabled me to support and advise his department as the first Scientific Intrapreneur in the history of the IZPT.
Do you also see yourself to be a sponsor and/or (scientific) intrapreneur? Then please feel free to contact me in person: .