Medha M. Pathak - US grants

Project Summary The importance of mechanics in biology is increasingly recognized in human health and disease. Mechanical cues are read, generated, and transmitted by biological systems and are essential for a wide range of cellular processes including cell fate and differentiation. The emerging field of Mechanobiology examines mechanical signaling across multiple scales from single molecules to whole organisms. The methods used to address this question are diverse and require multidisciplinary teams of engineers, physicists, biologists, and clinicians. However, existing gaps and barriers in information exchange, as well as cultural differences between these diverse scientific communities, limit progress. The ?Mechbio symposium: The Mechanome in Action? conference proposed here seeks to bring together researchers from multiple disciplines who work on mechanical signal transduction. The conference aims to unify researchers from a broad range of fields (physics, biology, chemistry, math, medicine, engineering) and with expertise in a wide variety of methodologies (theory, computation, and experiments) to encourage collaboration. The conference will be held on July 26-27, 2018, at the Sue and Bill Gross Stem Cell Research Center at the University of California, Irvine. The conference will be organized into 6 sessions with the following topics on Mechanobiology: Tissue Organization, Cell-Cell Interactions, Cell Fate & Differentiation, Bacterial Physiology and Host-Microbe interactions, Channels and Membranes, and Sensory Transduction. Each session will consist of talks by a student or postdoc, junior faculty, and keynote speaker. To facilitate new collaborations and scientific engagement among principal investigators and students, two interactive social sessions will be arranged: Science Speed-Meetings and Science Challenge: Mechanobiology Moonshot. Furthermore, to stimulate new scientific collaborations, Mechbio Opportunity Awards will be awarded that will support travel for a team of two to three graduate students to travel to the other respective lab to work on a new collaboration. To provide an inclusive atmosphere, speakers have been invited with consideration of gender, career stage and ethnic background, and childcare supplements, travel awards, and disability services will be offered. The University of California at Irvine is a leader in biomechanics and biophysics and will provide a stimulating environment for this symposium. In addition, the conference venue offers a modern and interactive environment in the heart of the UC Irvine campus. The site is 3 miles from John Wayne Airport (SNA) and is in close proximity to hotels, nature reserves, and beaches. Irvine is also in proximity to major universities with diverse student representation University of California campuses, the University of Southern California, Caltech and Stanford.

Mechanical signals are an important influence on the development, structure, and function of the central nervous system. Neural stem/progenitor cells (NSPCs), which generate neurons, astrocytes, and oligodendrocytes, are particularly sensitive to mechanical cues. During development, mechanical signals drive NSPC lineage specification, cell migration, and axon guidance. In stem cell transplant therapy, mechanical cues experienced by stem cells both in vitro before transplantation and in vivo after transplantation influence engraftment. Despite their manifest importance, the processes by which NSPCs detect, transduce, and generate mechanical forces remain poorly understood. Our overall objective is to uncover novel molecular mechanisms underlying NPSC mechano-regulation that could be harnessed for therapeutic strategies against neurodevelopmental and neurodegenerative diseases. We recently reported that the mechanically-activated ion channel Piezo1 generates Ca2+ flickers in NSPCs, and showed that its activity promotes differentiation into neurons rather than glia. Our new preliminary data also shows that Piezo1 knockout in mice results in gross abnormalities of the brain. Intriguingly, Piezo1 is active even in the absence of externally-applied mechanical force and this activity is triggered by cellular traction forces ? intracellular forces generated by the cell?s acto-myosin cytoskeleton to probe mechanical properties of the extracellular matrix. Here we examine the functional dynamics between traction forces and Piezo1 in NSPCs. Aim 1 examines how traction forces activate Piezo1; Aim 2 asks whether Piezo1 activity feeds back to modulate Myosin II activity; and Aim 3 examines the role of the mechanical signaling between Piezo1 and Myosin II in neural tissue mechanics during development. These studies will provide a mechanistic insight into Piezo1?s role in regulating NSPC behavior in vitro and in vivo.

Abstract: As the brain develops, proliferating cells organize into structures, differentiate, migrate, extrude long processes and connect with other cells. These biological processes produce mechanical forces that shape cellular dynamics and organ patterning. A major unanswered question in developmental biology is how the mechanical forces produced during development are detected and transduced by cells to impact the biochemical and genetic programs of development. New biophysical approaches are required to answer this question. We aim to uncover the mechanical dynamics underlying human neural development by generating new molecular, imaging and bioengineering tools. We will measure and manipulate mechanical forces at different timepoints of human brain organoid formation. These studies will provide quantitative and mechanistic insights on the role of mechanical forces during development, and demonstrate how development fails when they are disrupted.