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NIH grant 1R35GM166480-01: In action, in context, in situ - leveraging and advancing cryoimaging to uncover mechanisms of cell communication
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Luiza Mendonca. Award: $404165.
Start: 2026-07-23T00:00:00.
Project Summary
To understand the molecular basis of cellular function, it is essential to visualize biological
machinery in action and within its native context. This research program leverages in situ
correlative cryoimaging to open direct windows into the cell, revealing molecular events as
they natively occur. The program will advance this vision along two synergistic themes that
address both a fundamental biological question and a critical technical bottleneck in the field.
First, we will decode the in situ architecture of juxtacrine signalling, using the critical Notch
pathway as a primary model system. By applying our established correlative pipeline to
directly image Notch-ligand complexes at cell-cell interfaces, we aim to provide the first
molecular blueprint of this essential signalling machine, resolving longstanding questions
about its mechanism of action in a crowded cellular environment. Second, we will develop
next-generation tools for precision image registration in multimodal cryoimaging. To
overcome a major limitation in current cryogenic correlative light and electron microscopy
(cryoCLEM) workflows, we will engineer and validate a novel class of genetically-encoded,
intracellular fiducial markers based on vault ribonucleoproteins. These ‘microscopic
beacons’ are designed to provide robust, unambiguous reference points for cryoCLEM,
dramatically improving targeting accuracy and the overall efficacy of in situ cryoimaging
pipelines. Collectively, these efforts will not only provide unprecedented insights into a
disease-relevant signalling pathway but will also deliver transformative and broadly
applicable tools to the structural and cell biology community. By advancing our ability to see
and understand the cell's inner workings in situ, this program will help pave the way for new
avenues of biomedical discovery.document fetched 2026-08-02 08:24