Project

Discipline

Stem cells; Pre-clinical study; Bullous Diseases; Cell-Cell Adhesion; Atomic Force Microscopy; Cell signaling; Biophysical signaling; Autoimmune disease

Lead
Die bemerkenswerte Komplexität der Morphogenese und Geweberegeneration impliziert die Existenz eines transzellulären Kommunikationsnetzwerks, indem einzelne Zellen die Umgebung wahrnehmen und ihre biologische Aktivität in Raum und Zeit koordinieren. Das ganzheitliche Verständnis der faszinierenden Fähigkeit des Gewebes sich selbst zu organisieren ist ausstehend. Wissenschaftler gehen davon aus, dass das "Knacken des transzellulären Kommunikationscodes" die umfassende Untersuchung und Integration biophysikalischer Eigenschaften (zelluläre Nanomechanik und Bioelektromagnetik) in biochemische und genetische Netzwerke voraussetzt.Diese Aufgabe stellt sich dieses Projekt.
Lay summary
Eine wichtige Rolle der Integration biophysikalischer Signale in biochemische und genetische Netzwerke spielen Zell-Matrix- und Zell-Zell-Adhäsionsmoleküle. Eine unerwartet prominente Funktion der desmoglein 1/3-vermittelten Adhäsion in diesem Prozess hat die Gruppe vor kurzem mittels Analysen der lebensbedrohenden, blasenbildenden Autoimmunen Erkrankung pemphigus vulgaris identifiziert. Ausgehend von der krankmachenden Modulation der desmoglein 1/3 Adhäsion durch Autoantikörper hat das Projekt zum Ziel, zeitlich korrelierte biophysische, biochemische, epigentische und genetische Veränderungen in Stammzellen, die für die Geweberegeneration zentral wichtig sind, minutiös zu erheben und mittels integrativer Datenanalysen zu einem ganzheitlichen Kommunikationscode zusammenzufügen. Zur Anwendung kommen dabei innovative Mikroskopiermethoden der Biophysik (Fluid Force Microscopy) sowie ganzheitliche OMICS Analysen der Zell- und Molekularbiologie, die der Systembiologischen Integration vorausgehen, deren Relevanz in Gewebemodellen und pemphigus vulgaris Patienten validiert wird.   Das Projekt befasst sich mit klinisch angewandter Forschung auf der Basis eines Systembiologischen Ansatzes. Wir erwarten, dass das Ergebnis einen Paradigmenwechsel im Verständnis der Adhäsionsmoleküle in der transzellulären Kommunikation und Geweberegeneration zur Folge hat. Diese Erkenntnisse werden direkt der Entwicklung neuer, dringend benötigter Behandlungsansätze für pemphigus vulgaris Patienten sowie anderer schwerer entzündlichen und neoplastischen Erkrankungen des Menschen zugutekommen.

Direct link to Lay Summary

Last update: 10.06.2021

Natural persons

Number	Title	Start	Funding scheme

The remarkable complexity of morphogenesis and tissue regeneration implies the existence of a transcellular communication network in which individual cells sense the environment and coordinate their biological activity in time and space. The understanding of the fascinating ability of tissue self-organization is still rudimentary. Scientists now conceive that “cracking the transcellular communication code” requires the comprehensive study of biophysical properties (cellular nanomechanics such as tension forces and bioelectromagnetics) in combination with the analysis of biochemical networks (signaling pathways and genetic circuits). A major role in integrating tension forces into biophysical and biochemical networks is emerging for cell-matrix and cell-cell adhesion molecules; integrins and classical cadherin-type adhesion receptors have been identified as transmitters of physical signals from the extracellular space to the cytoskeleton, ion channels and selected signaling pathways. Surprisingly, in quest of the transcellular communication code, research into desmosomal cadherin-type adhesion molecules is only starting to emerge in spite of their suggested outside-in signaling activity and critical role in bearing mechanical tissue stress. However, one report linking a specific biochemical signaling component to altered tissue stiffness, a well-known mechanical read-out, highly supports such an activity in cells treated with pemphigus vulgaris (PV) autoantibodies capable to disrupt desmosomal cadherin transadhesion. Pemphigus is a unique group of autoimmune diseases. Desmoglein 3 (Dsg3) or Dsg1/3 are the major targets in PV expressed in epidermal and hair follicle stem and progenitor cells as well as in mucous membranes. We and others have demonstrated that antibody-induced disruption of Dsg3 transadhesion initiates a signaling response in basal (stem and progenitor) keratinocytes followed by loss of tissue integrity. Moreover, unlike for classical cadherins, our recent investigations now reveal that loss of functional Dsg3 results in stem cell fate conversion, plasticity and tissue repair. These results are in line with increased proliferation of basal keratinocytes in PV patients which supports our hypothesis of an unacknowledged key role of Dsg3 in mechanosensing and -signaling. Our consortium of cellular and systems biologists, dermatologists and physicists with recognized expertise in PV pathophysiology, cell-cell adhesion and biophysical processes, supported by geneticists proposes to apply cutting-edge technologies on PV as a model with the target to establish a comprehensive and integrative biophysical and biochemical Dsg3 signaling network to define the clinically relevant, transcellular tissue communication code driving tissue remodeling during injury. Our goals are: 1) to apply innovative Fluid Force Microscopy to measure altered biophysical parameters upon disruption of Dsg3 transadhesion such as cell stiffness, surface charges and electric potentials 2) to relate longitudinal biophysical changes to transcriptomic, epigenomic and proteomic response circuits 3) to infer biophysical and biochemical circuits involved in Dsg3 signaling based on integrative data analysis and modeling supported by chemical or biological inhibitors/activators and exogenous field manipulations 4) to confirm causal changes in pre-clinical PV model systems and PV patientsWe expect the outcome to introduce a real paradigm-shift in the understanding of both desmosomal and classical cadherin-mediated self-organized transcellular communication and tissue remodeling. These insights will have a direct impact on the development of novel, highly needed treatment approaches, which will benefit not only PV, but also other severe human inflammatory and neoplastic diseases.