FOR 1738:  Heme and Heme Degradation Products (HHDP): Alternative Functions and Signalling Mechanisms

• Subject Area: Medicine ; Chemistry
• Term: from 2012 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 198096916

Heme is a well-known prosthetic group of various proteins. Heme degradation products (HDPs), such as carbon monoxide (CO), biliverdin, and bilirubin, are foremost thought as toxic and unwanted waste products that our body must eliminate. However, recent studies suggest that induction of heme oxygenase and CO administration are beneficial for the treatment of disorders associated with pathophysiological heme liberation, and elevated unconjugated heme levels under pathophysiological conditions impair disease tolerance. Moreover, the compelling preliminary results from this research consortium show that heme and heme degradation products (HHDPs) are cellular signaling molecules that profoundly alter multiple aspects of body function. Dysregulation of HHDP-related signaling has serious and potentially deadly consequences including stroke and sepsis, and ion channels are relevant molecular mediators. A limiting factor in studying the role of HHDPs, however, is their complex or labile nature, and strategies for their chemical synthesis or methods for their quantitative detection in living cells or body fluids are only beginning to become available. Our paradigm-shifting postulate, attributing signaling and pathophysiological roles to HHDPs, will therefore be critically evaluated using an interdisciplinary approach. In a team of researchers from diverse institutions and scientific fields, comprising clinical medicine, molecular physiology and biophysics, biochemistry, biophotonics, as well as synthetic and analytical chemistry, we will elucidate mechanistic principles of HHDP actions. We will address integrated systems as well as ion channels with an approach that involves the use of novel reagents and cutting-edge methodologies. The anticipated synergistic research outcome of our proposal will have a profound and wide impact on the understanding of heme-related cell signaling, of heme decomposition as well as molecular properties of its catabolites, and will break new ground in clinical medicine.

• DFG Programme: Research Units
• International Connection: USA

Projects

• Central tasks and administration of the Research Unit FOR 1738 (Applicant Heinemann, Stefan H. )
• CO regulation of Slo1 BKCa potassium channels (Applicant Hoshi, Toshinori )
• Ex-vivo and in-vivo spectroscopic characterization and detection of heme and heme degradation products (Applicants Neugebauer, Ute ;  Popp, Jürgen )
• Heme and heme degradation products as effectors of hepatic perfusion and excretion failure (Applicant Bauer, Michael )
• Impact of heme and heme degradation products on acute kidney injury associated with Shiga toxin 2-induced hemolytic-uremic syndrome (Applicant Coldewey, Ph.D., Sina Maren )
• Impact of heme and heme degradation products on peptides and proteins (Applicants Imhof, Diana ;  Ohlenschläger, Oliver )
• Impact of heme and heme degradations products on cerebral vascular reactibility (Applicant Witte, Otto Wilhelm )
• Regulation of voltage-gated potassium channels by HHDPs (Applicant Heinemann, Stefan H. )
• Synthesis and analytics of HHDPs (Applicant Pohnert, Georg )
• Synthesis and functional evaluation of carbon monoxide releasing molecules (CORMs) and materials (CORMAs) (Applicant Westerhausen, Matthias )

• Spokesperson: Professor Dr. Stefan H. Heinemann