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Photon-Efficient Spectral Lifetime Microscopy

Award Number: R35GM166021
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Photon-Efficient Spectral Lifetime Microscopy - PROJECT SUMMARY Disentangling mixed molecular species and multi-component signaling in complex cellular environments remains a fundamental challenge for fluorescence microscopy. While advanced microscopy techniques have been transformative for imaging at the limits of spatial resolution with low phototoxicity, current methods still permit the use of only a few fluorescent probes at a time, typically separated by their emission wavelength. This constraint fundamentally limits the throughput of biophysical measurements and our ability to simultaneously monitor multiple interacting signals. Fluorescence lifetime provides an orthogonal axis of information that can increase the dimensionality and information content of fluorescence images, but traditional approaches have been limited by low photon throughput and high technical complexity. This proposal will develop the optical technology necessary to unlock a high dimensional space for multiplexed imaging of fluorescent signals by leveraging a combination of photon-optimal fluorescence lifetime and spectral imaging approaches. These technologies will exploit the nanosecond time dimension to achieve physical limits of multiplexing performance set by the constraints of the probe molecules and shot noise. Multiplexed single molecule imaging will be used to explore the limits of information per photon that can be achieved in a fluorescence microscopy experiment. Single molecules provide an ideal benchmark for establishing these technologies and enable applications in super-resolution localization microscopy and efficient barcoding of molecular species. Moving into more crowded molecular environments, the same optical approaches will be used to unmix functional signals in live cell imaging to enable simultaneous quantitative measurement of membrane potential and intracellular metabolic dynamics, revealing relationships between cellular energetics, stress, and electrical excitability. Finally, these tools will be applied to quantitatively unmix dynamic signals in vivo to record the spatial and temporal relationships between membrane potential and downstream intracellular and extracellular signals in noisy environments. Together these approaches will enable high-dimensional imaging across sample types ranging from the molecular to tissue scale and across orders of magnitude of sample brightness. The nanosecond imaging and multiplexing tools developed here achieve fundamental limits of information available per fluorescence photon and will be broadly enabling across imaging contexts and model systems. Notably these techniques may be added to any existing microscope platform using standard scientific camera sensors, making them widely available and easily adopted by the scientific community.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $475,249 )
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	8/6/2026	NEW	$475,249
														Subtotal = $475,249

Grand Total All Awards = $475,249

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Photon-Efficient Spectral Lifetime Microscopy

Award Number: R35GM166021

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/10/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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