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Whole organ transcriptome reconstruction by dimensionality reduced fluorescent in situ hybridization

Award Number: R01HG012925
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Whole organ transcriptome reconstruction by dimensionality reduced fluorescent in situ hybridization - Project Summary In biology, structure determines function. To understand the function of organs (i.e., physiology), we must obtain structural information on the organs’ structure (i.e., anatomy). Mapping organs’ structures must occur at (sub)cellular spatial resolution with sufﬁcient details on cells’ molecular states. Spatial transcriptomics technologies have made signiﬁcant advances in mapping thin tissue sections. However, all spatial transcriptomics approaches are restricted to sections thinner than 150 µm, with the vast majority needing to be less than 15 µm. While 2D sections are informative, sampling 3D organs with 2D sections loses information and provides a partial view of the organs’ full structure. Here we propose to develop whole organ spatial transcriptomics. Key to our approach is our recent invention (patent pending) of dimensionality reduced Fluorescent In Situ Hybridization (dredFISH). Single-molecule FISH approaches, such as smFISH, MERFISH, seqFISH+, and many other variants, label and count individual RNAs. dredFISH is not a single molecule FISH. Instead, it is designed to directly measure an approximation of cells’ transcriptional state by measuring multiple distinct weighted sums of thousands of genes. The transcriptional signatures represented by the distinct sums of genes are generated for the reference scRNAseq and compared to the ones directly measured by dredFISH. Integrating and harmonizing the directly measured FISH signatures and the reference data allows the inference of cell types (kNN classiﬁcation) and gene expression reconstruction (kNN regression). By leapfrogging the need for individual gene measurements, dredFISH achieves multiple features that make it ideal for fast light-sheet microscopy of thick samples (500 µm). Speciﬁcally, i) dredFISH is performed using low magniﬁcation objectives (10x, 16x) instead of high magniﬁcation objectives (60x,100x) used for single-molecule FISH. ii) dredFISH utilizes the tissue clearing and hydrogel embedding technique used by CLARITY, making it compatible with existing light-sheet imaging protocols. iii) dredFISH signal comes from the weighted sums of ﬂuorescence from tens of thousands of RNA molecules per cell, each stained by tens of probes, making it much brighter and easier to measure than all other FISH approaches. Our preliminary results demonstrate that dredFISH works well in thin 2D sections validating our approach. The goal of this proposal is to extend dredFISH from 2D to 3D to allow whole organ spatial transcriptomics. This goal will be accomplished by parallel development steps divided into two aims. Aim #1 will continue optimizing and validating dredFISH in 2D by changing a few aspects of the method that will ease the transition to 3D. Aim #2 will update the staining and imaging steps in the dredFISH protocol to make them compatible with thick samples. Aim #3 will demonstrate the power of dredFISH whole organ spatial transcriptomics by creating the entire mouse brain's cell type and gene expression atlases. By completing these aims, we will deliver new capabilities: whole organ spatial transcriptomics that will have transformative effects on numerous biomedical disciplines.


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 = $626,979 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	000	3	3/9/2026	NON-COMPETING CONTINUATION	$626,979
														Subtotal = $626,979

Issue Date FY: 2025 ( Subtotal = $618,766 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	000	2	3/6/2025	NON-COMPETING CONTINUATION	$556,890
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	001	2	4/28/2025	NON-COMPETING CONTINUATION	$61,876
														Subtotal = $618,766

Issue Date FY: 2024 ( Subtotal = $643,781 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	000	1	5/6/2024	NEW	$583,927
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	001	1	8/1/2024	NEW	$59,854
														Subtotal = $643,781

Grand Total All Awards = $1,889,526

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Whole organ transcriptome reconstruction by dimensionality reduced fluorescent in situ hybridization

Award Number: R01HG012925

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/06/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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