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DTSTART:20241022T090000Z
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TRANSP:OPAQUE
LOCATION:Auditorium
SUMMARY:ICFO | LUKAS DOMINIK LAU
CLASS:PUBLIC
DESCRIPTION:This thesis explores the molecular mechanisms underpinning leuk
 ocyte adhesion and migration\, with a primary focus on the mechanobiology 
 of integrin Lymphocyte function-associated antigen 1 (LFA-1). Integrins ar
 e key mediators of cell adhesion\, which are pivotal in immune response an
 d facilitate leukocyte adhesion\, migration\, and extravasation at infecti
 on sites. This thesis begins by summarizing the structural characteristics
  of integrins\, their mechanobiology and the physiological processes invol
 ved in LFA-1 activation\, emphasizing the roles of chemokines\, adaptor pr
 oteins\, and tensile forces in modulating integrin function.\nThe experime
 ntal research employs advanced single-particle tracking (SPT) using a home
 -built live-cell microscope with single molecule sensitivity. This multili
 ne-illumination dual-view microscope\, combined with a custom-built flow s
 ystem\, enables the investigation of LFA-1 activation at the level of indi
 vidual molecules under shear flow. We use specific surface functionalizati
 on to provide the appropriate stimuli and interaction partners for leukocy
 te adhesion and migration.\nThe study highlights the characteristics of LF
 A-1 mobility and engagement\, showing how it is regulated by various stimu
 li\, including physiological chemokines like CXCL12 and divalent cations s
 uch as Mn2+. The critical role of adaptor proteins\, particularly talin\, 
 in mediating the integrin-actin cytoskeleton linkage essential for leukocy
 te motility\, is also examined. The findings underscore the importance of 
 integrin ligation and cytoskeletal association in integrin activation for 
 effective leukocyte migration\, highlighting the need for precise spatiote
 mporal control of integrin engagement for leukocyte motility.\nWe further 
 dissect the impact of external tensile forces\, such as shear flow\, on in
 tegrin activation. We demonstrate that these forces significantly increase
  integrin activation\, consequently reinforcing cell adhesion and migratio
 n under varying flow conditions. The study also reveals the complex interp
 lay between biochemical stimuli and mechanical forces in modulating integr
 in activation and consequently leukocyte behavior. In this context\, we ad
 ditionally we bring attention to the relevance of adaptor proteins like ta
 lin.\nFinally\, we shift focus to the spatiotemporal relationship between 
 the C-X-C chemokine receptor type 4 (CXCR4) and LFA-1. The focus lies on t
 he functionally relevant CXCR4 nanoclustering and its vicinity to LFA-1 ac
 tivation. We uncover unexpected behaviors in functional CXCR4 nanoclusteri
 ng and investigate its spatial relation to integrin activation. The study 
 extends to both healthy CXCR4 and a pathologically altered form\, a R334X 
 mutation found in patients with Warts\, Hypogammaglobulinemia\, Infections
 \, and Myelokathexis (WHIM) syndrome.\nThe thesis concludes by synthesizin
 g these findings\, emphasizing the critical role of mechanobiology in leuk
 ocyte migration and the complex regulatory mechanisms governing integrin a
 ctivation. By providing a detailed framework for understanding integrin dy
 namics\, the research points towards its potential implications for pathop
 hysiological alterations of the blood flow and the potential for further s
 tudies using advanced biophysical techniques to unravel the intricate mole
 cular interplays at work. Future perspectives include investigating the in
 terplay of the regulatory network for integrin activation\, the impact of 
 integrin ligand organization\, and the effect of mechanical forces on the 
 relevant players. The insights gained from this work could pave the way fo
 r novel therapeutic strategies that target the mechanobiological aspects o
 f immune cell motility\, offering new avenues for the treatment of inflamm
 atory diseases and immune-related disorders where aberrant cell adhesion a
 nd migration plays a critical role.\n&nbsp\;\nTuesday October 22\, 11:00h.
  ICFO Auditorium \nThesis Director: Prof. Dr. Mar&iacute\;a Garcia-Parajo
DTSTAMP:20260407T073818Z
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