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A Bayesian nonparametric approach to superresolved tracking of multiple molecules inside living cells

Award Number: R01GM130745
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: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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A Bayesian nonparametric approach to superresolved tracking of multiple molecules inside living cells - Project Summary: The 2014 Chemistry Nobel Prize was awarded for advances in ﬂuorescent labeling, instrumentation and anal- ysis methods which together, over the last decade, have resolved particle positions to within ≈20-30 nm. That is, below the diffraction limit of light used to excite them. Superresolution has subsequently been used to image β-amyloid ﬁbers tied to neurodegenerative disorders and directly observe diffraction limited protein clustering linked to cancer phenotypes. While superresolved localization reveals static cellular structures of immediate relevance to health, it does not provide direct insight into disease dynamics. Directly observing in vivo dynamics at the single molecule level demands multi-particle superresolved particle tracking. Superresolved tracking is more difﬁcult than superresolved localization because – for the same number of photons collected – tracking requires mobile particles to be localized over multiple image frames. Furthermore, multi-particle superresolved tracking re- quires that this all be done while accounting for unavoidable overlapping particle trajectories within a conﬁned cellular volume a few diffraction limited volumes in size. Thus, to date, there is no systematic way to accurately track more than one protein, of the millions of proteins, inside a volume the size of E. coli’s cytoplasm at once. The overarching goal is therefore: To provide the ﬁrst principled multi-particle superresolved track- ing algorithm by exploiting the novel tools of Bayesian nonparametrics (BNPs) that have already deeply impacted Data Science over the last decade. BNPs can learn particle numbers in each frame and particle trajectories across all frames in a computationally tractable manner in a way that is directly informed by the data (photons collected per pixel). The tracking method developed will be applied to multi-particle problems – such as the assembly/disassembly of serine chemoreceptor, Tsr, complexes on E. coli’s inner membrane – and problems involving abrupt dynamical changes – such as transitions between bound/unbound states of RNA polymerases – naturally dealt with in the principled tracking framework proposed. Two Speciﬁc Aims are proposed. Speciﬁc Aim I – Develop the very ﬁrst, fully-integrated and unsupervised, superresolved tracking algorithm for multiple diffraction-limited particles under the assumption that particles diffuse with a single (unknown) diffusion coefﬁcient. Speciﬁc Aim II – Repeat Speciﬁc Aim 1 for the case where dynamical models according to which particles evolve are unknown or even changing in time (that is, the restriction that dynamics be governed by simple diffusion is lifted). Within each Aim, we will: determine particle numbers in each frame by adapting (nonparametric) Bernoulli processes; adapt observation models to account for complex label photophysics and aliasing artifacts important for fast-moving particle; treat particle conﬁnement for particle diffusion in small bacterial cells while learning dynamical models by adapting Dirichlet processes; incorporate detailed camera noise models.


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: 2025 ( Subtotal = $0 )
2025	2023	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Biomedical Research and Research Training	000	5	4/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $299,572 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	5	12/7/2022	NON-COMPETING CONTINUATION	$269,614
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	5	2/16/2023	NON-COMPETING CONTINUATION	$29,958
														Subtotal = $299,572

Issue Date FY: 2022 ( Subtotal = $300,640 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	4	11/11/2021	NON-COMPETING CONTINUATION	$270,576
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	4	6/27/2022	NON-COMPETING CONTINUATION	$30,064
														Subtotal = $300,640

Issue Date FY: 2021 ( Subtotal = $301,630 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	3	2/25/2021	NON-COMPETING CONTINUATION	$30,163
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	3	10/30/2020	NON-COMPETING CONTINUATION	$271,467
														Subtotal = $301,630

Issue Date FY: 2020 ( Subtotal = $302,546 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	2	3/10/2020	NON-COMPETING CONTINUATION	$30,255
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	2	11/21/2019	NON-COMPETING CONTINUATION	$272,291
														Subtotal = $302,546

Issue Date FY: 2019 ( Subtotal = $302,865 )
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	1/28/2019	NEW	$302,865
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	1	2/22/2019	NEW	$0
														Subtotal = $302,865

Grand Total All Awards = $1,507,253

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A Bayesian nonparametric approach to superresolved tracking of multiple molecules inside living cells

Award Number: R01GM130745

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: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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