PROJECT SUMMARY Cell behaviors and tissue developments often occur under spatial constraints (e.g., interstitial space, tissue lining, skull enclosure). The current in vitro systems are often open cultures, and thus miss the spatial constraints and other in vivo stimuli. The current in vivo models are often low throughput and hard-to-trace, therefore unable to unravel the complex interplay between intrinsic influences (e.g., genetics/epigenetics) and extrinsic ones (e.g., micro-environment). For example, cell membrane blebbing and brain folding are fundamental and impactful bio-behaviors under spatial constraints. Their biophysical and molecular mechanisms are not well understood. Lately, several experimental and theoretical tools have emerged to fascinate the modeling of complex bio-behaviors. This proposed study aims to parameterize morphological information, relate to the complex influences under spatial constraints, and unravel the mechanism of bio- behaviors in the two exemplified areas. It will be done through a morphome platform that integrates several experimental-theoretical tools (e.g., tissue-on-a-chip, data-driven modeling, machine-learning), which has been pre-defined by PI and Co-Is. We hope to 1) fill the compelling gaps in our understanding of membrane blebbing and brain folding process and 2) establish an effective strategy to uncover a broad range of basic biological processes.