# High Resolution Characterization of Receptor Signaling and Regulation

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $408,584

## Abstract

Project Summary
This continuing research is aimed at characterizing, at micro- and nanoscales, the collective molecular events
of cellular signaling that are initiated by plasma membrane receptors or ion channels and are highly
orchestrated in space and time. Mast cells, which are stimulated by IgE-receptors and play a pivotal role in
immune responses, serve as a valuable model system for investigating basic mechanisms by which cells
respond to specific stimuli in a noisy environment. Proposed research will build on established thrusts: 1)
Delineate with increasing resolution the initiation of stimulated cell signaling with a focus on critical but subtle
events occurring at cellular membranes; 2) Translate the advanced technologies and refined hypotheses we
have developed in model cells to disruption of cellular processes associated with neurodegenerative diseases.
Innovative aspects include advancing an imaging modality of fluorescence correlation spectroscopy (ImFCS) to
measure dynamic interactions of signaling-related components within the heterogeneous plasma membrane.
The large data sets and robust analytics afforded by ImFCS yield precise values for multi-component diffusion
and transient confinement parameters, revealing subtle interactions experienced by selective probes. This and
other quantitative fluorescence microscopies will be used to evaluate constitutive and stimulated formation of
kinase complexes, membrane trafficking, and mitochondrial dynamics, which are disrupted in cellular
pathologies. Specific Aim 1 will implement ImFCS to measure diffusion properties of transmembrane proteins
and proteins anchored to plasma membrane inner and outer leaflets to reveal distinctive environments
experienced by these probes before and after antigen-crosslinking of IgE-receptors to initiate transmembrane
signaling. We will measure stimulated changes in seconds timescale and collaboratively adapt theoretical
models to interpret our results in terms of time-dependent changes of IgE-FcεRI cluster size as related to early
signaling events. Specific Aim 2 will collaboratively investigate model cells to gain mechanistic insight into cell-
based pathologies associated with neurodegeneration. Building on established phenotypes, we will continue to
evaluate structural features of α-synuclein variants that disruptively modulate membrane trafficking and
mitochondrial activities in Parkinson’s disease. We will use micro-patterned surfaces and ImFCS to yield new
understanding of microglia-mediated hydrolysis of Aβ fibrils that goes awry in Alzheimer’s disease and
phosphatidyl inositol kinase complexes that are disrupted in hypomyelination diseases.

## Key facts

- **NIH application ID:** 9838516
- **Project number:** 2R01GM117552-36
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Barbara A Baird
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,584
- **Award type:** 2
- **Project period:** 1981-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838516

## Citation

> US National Institutes of Health, RePORTER application 9838516, High Resolution Characterization of Receptor Signaling and Regulation (2R01GM117552-36). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838516. Licensed CC0.

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