Structure, function, and mechanobiology of a compression-sensitive cell-cell junction

Project Description and Summary The goal of this proposal is to characterize a newly identified cadherin-mediated cell-cell junction, and understand the contexts in which it functions. The cooperation between adhesions and mechanical forces is a central regulator of many developmental and homeostatic processes that has been studied for over half a century across a wide variety of biological contexts. In particular, the assembly of junctional complexes triggered by mechanical tension – a phenomenon known as adhesion strengthening – is widely conserved across a diverse range cell-matrix and cell-cell adhesion receptors, such that it has been suggested that it may be the only type of response in present day living systems. However, the investigator has recently discovered a cadherin-mediated cell-cell junction that is characterized by a distinct composition and the ability to assemble in response to compressive forces. Here, the investigator will identify the molecular components, organizational structure, underlying force-responsive mechanisms, and cellular impact of this previously unappreciated junctional complex, and elucidate the biological contexts in which this pathway is engaged. These objectives will be achieved through an interdisciplinary research effort built around three Aims: Specific Aim 1 will be to define the structure and molecular participants of this compression sensitive, cadherin- mediated cell-cell junction. Specific Aim 2 will investigate the molecular mechanisms, mechanics, and dynamics regulating the cell-cell junction. Specific Aim 3 will be to explore the extent to which these junctions contribute to a range of biological contexts where junctions are known to be important, including lymphatic drainage function and sorting morphogenesis. Together, these studies will offer critical insights into an important new type of cell-cell junction that uniquely assembles with compression, and thereby add a new chapter in cell adhesion biology. Project Number: 1R01HL175072-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: CHRISTOPHER CHEN | Institution: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS), BOSTON, MA | Award Amount: $644,180 | Activity Code: R01 | Study Section: Cell Structure and Function 1 Study Section[CSF1] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17507201A1