TRR 152:  TRiPs to Homeostasis: Maintenance of Body Homeostasis by Transient Receptor Potential Channel Modules

• Subject Area: Medicine
• Term: since 2014
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239283807

Transient receptor potential (TRP) channels represent an extended and diverse protein family fulfilling salient roles as versatile cellular sensors and effectors. The fundamental role of TRP channels in sensory processes has been highlighted by The Nobel Prize in Physiology or Medicine 2021. TRP proteins control an exceptionally broad spectrum of homeostatic physiological functions, illustrated by more than 20 hereditary human diseases caused by mutations in 14 Trp genes. Most TRP channel-related human disorders impinge on development, metabolism and other homeostatic functions. There is accumulating evidence to link TRP channels to even more human diseases beyond TRP channelopathies, and accordingly, TRP proteins have been identified as appealing therapeutic targets. Drawing on previous conceptual achievements and a unique TRP channel toolbox containing mouse models, specific antibodies, drug-like small molecules, and advanced experimental protocols, the CRC focuses on the overarching aim to validate TRP channels as new therapeutic targets. The following three challenges will be met: (1) There is a pressing need to further our understanding of the (patho)physiological role of TRP channels and their exact contribution to cellular, tissue and organismal homeostasis and dysfunction. (2) Applying new molecular approaches like single-particle cryo-electron microscopy along with advanced AI-based in silico methods, in-depth biophysical analyses, and medicinal chemistry, we will refine specific (photo-switchable) chemical probes to limit potential off-target and off-tissue side effects of drug-like small molecules. (3) To foster early clinical translation, reliable and robust pre-clinical disease models will be developed including genetically modified mouse models, in vitro human-derived organoids, and engineered human tissue. Three central questions will be addressed:(1)What are the building blocks of native TRP channels in defined tissues/cells and how do the components of TRP channel modules interact functionally in defined cellular compartments?(2)What is the physiological role of TRP channels in vivo and what is the precise mechanism of their activation and regulation?(3)What are the detailed pathomechanisms underlying human diseases caused by dysfunctional TRP proteins and which translational perspectives can be derived?Such fundamental insight will blaze the trail for specific, tailored treatment options for patients suffering from diseases inflicted by (dysfunctional) TRP proteins.

• DFG Programme: CRC/Transregios

Current projects

• P02 - Structure, assembly and function of TRPC and TRPM7 channels in complex with newly identified interaction partners (interactome constituents) (Project Heads Fakler, Bernd ;  Raunser, Stefan ;  Schulte, Uwe )
• P03 - Functional characterization of the TRPP2 channel complex (Project Head Köttgen, Michael )
• P04 - Endolysosomal cation channels in synucleo- and tauopathies (Project Head Grimm, Christian Michael )
• P07 - TRPC channels in synaptic short-term plasticity and secretion (Project Heads Bruns, Dieter ;  Schwarz, Ph.D., Yvonne )
• P10 - Novel TRP channel functions in olfaction (Project Heads Leinders-Zufall, Trese ;  Zufall, Frank )
• P11 - Windows into the brain: Genetic analyses of TRP-channel function(s) in the homeostasis control center (Project Head Boehm, Ulrich )
• P12 - Exploring TPC2 as target for age-dependent macular degeneration therapy (Project Heads Biel, Martin ;  Michalakis, Stylianos )
• P14 - The kinase-coupled TRPM7 channel as a regulator of immune system homeostasis (Project Head Zierler, Susanna )
• P15 - Role of kinase-coupled TRP channels in mineral homeostasis of the brain (Project Heads Chubanov, Ph.D., Vladimir ;  Gudermann, Thomas )
• P16 - Role of TRP channels in barrier function and pathological remodeling of the respiratory system (Project Head Dietrich, Alexander )
• P17 - Patient-specific induced pluripotent stem cell models to elucidate the role of TRPM4 channels in the pathogenesis of inherited cardiac arrhythmia (Project Heads Laugwitz, Karl-Ludwig ;  Lipp, Ph.D., Peter ;  Moretti, Ph.D., Alessandra )
• P18 - The role of TRPV2 and TRPV3 in epithelial barrier homeostasis (Project Heads Hill, Kerstin ;  Schaefer, Michael )
• P20 - The role of TRP channels in heat acclimation (Project Head Siemens, Jan )
• P21 - Functional and molecular specificity of OCaR-control of intracellular Ca2+ release (Project Heads Freichel, Marc ;  Schulte, Uwe )
• P22 - TRPM5: a new target for the resolution of airway inflammation (Project Head Krasteva-Christ, Gabriela )
• P23 - Role of TRP channels in the systemic regulation of energy and glucose metabolism (Project Heads Khajavi, Noushafarin ;  Müller, Timo ;  Tschöp, Matthias )
• P25 - The role of TRPP2 in the pathogenesis of polycystic kidney disease and primary cilia signaling (Project Head Mick, David )
• P26 - Investigating the mechanisms and dynamics of TRPC channel activation with pharmacological high-precision tools (Project Heads Konrad, David ;  Storch, Ursula )
• P27 - TRP channels as regulators of autoimmune CNS inflammation (Project Heads Kerschensteiner, Martin ;  Peters, Anneli )
• P28 - Role of TPC2 in cellular signaling networks (Project Head Wahl-Schott, Christian )
• Z01 - Administration / Guests / Travel / Gender Equality (Project Head Gudermann, Thomas )
• Z02 - The trp zoo: a combinatorial genetic approach to visualize and manipulate TRP-expressing cells (Project Heads Boehm, Ulrich ;  Flockerzi, Veit )

Completed projects

• P01 - TRPC1 function in Ca2+ homeostasis (Project Head Flockerzi, Veit )
• P05 - Proteomic analysis and physiological function of the two pore channel TPC1 (Project Heads Klugbauer, Norbert ;  Schulte, Uwe )
• P06 - Role of TPC2 in cellular signaling networks (Project Head Wahl-Schott, Christian )
• P08 - Role of TRPC6 channels in hippocampal function and plasticity (Project Heads Hartmann, Jana ;  Konnerth, Arthur )
• P09 - Functional role of TRP channels in neuroendocrine cells of the brain (Project Head Leinders-Zufall, Trese )
• P13 - Physiological function of the TRPV6 protein in placenta (Project Heads Fecher-Trost, Claudia ;  Weißgerber, Petra )
• P19 - Exploring the pharmacology and photopharmacology of TRP channels (Project Heads Magauer, Thomas ;  Trauner, Dirk )
• P24 - Reagents for spatiotemporal control over TRPM/TRPC function (Project Head Thorn-Seshold, Oliver )

• Applicant Institution: Ludwig-Maximilians-Universität München
• Co-Applicant Institution: Universität des Saarlandes
• Participating University: Albert-Ludwigs-Universität Freiburg; Ruprecht-Karls-Universität Heidelberg; Technische Universität München (TUM); Universität Leipzig
• Participating Institution: Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Max-Planck-Institut für molekulare Physiologie
• Spokesperson: Professor Dr. Thomas Gudermann