Ph.D., Leipzig University, Leipzig, Germany, 2000
Cyclic nucleotide signaling and cAMP phosphodiesterases
Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that regulates a myriad of physiological processes. Its cellular concentration is determined by the rate of its synthesis by adenylyl cyclases and the rate of its degradation by cyclic nucleotide phosphodiesterases (PDEs). The mammalian PDEs encompass a large number of isoenzymes grouped into eleven families. Our laboratory explores the structure, regulation and physiological functions of Type 4 PDEs (PDE4s), the largest and most widely expressed PDE family.
The PDE4 family comprises four genes, PDE4A-D, that together are expressed as more than 25 protein variants. PDE4 inactivation produces a number of therapeutic benefits, including anti-inflammatory and memory- and cognition-enhancing effects, and has been pursued as a therapeutic approach for a number of indications. However, the non-selective PDE4 inhibitors available to date also produce significant side effects that limit their clinical utility. Individual PDE4 variants exert unique and non-overlapping physiological and pathophysiological roles by controlling cAMP levels in microdomains of signaling, to which they are tethered via variant-specific protein/protein or protein/lipid interactions, rather than on the global cellular scale. Our group aims to dissect the roles of individual PDE4 variants in diverse cells and tissues to verify individual PDE4s and PDE4 signaling complexes as drug targets. In addition, we explore regulatory and structural differences between individual PDE4s for the development of isoform-selective PDE4 inhibitors with an improved safety profile compared to the non-selective PDE4 inhibitors available to date.
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