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Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects

Award Number: P01HD104435
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/11/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects - PROJECT SUMMARY The unifying theme of this proposal is the aim to use state-of-the-art technologies to investigate the basic biology of mammalian organ development and human structural birth defects. Our approach is wide-ranging, and aims to demonstrate how utilization of powerful technologies can inform many disorders. Importantly, this proposal marries a number of strengths of investigators at Seattle Children’s Research Institute and the University of Washington Department of Genome Sciences; specifically, expertise in the diagnosis and understanding of human congenital malformation syndromes and mammalian developmental biology, and the application of powerful new techniques for biological investigation. In Project 1, we propose to use single-cell RNA sequencing (sci-RNA-seq) technology to characterize mid- gestation embryos of mice carrying mutations relevant to human structural birth defects. Essentially, we are proposing to utilize sci-RNA-seq as a phenotype, with which one can annotate changes in expression and cell- type representation during abnormal organogenesis. Ideally, these profiles will be comparable to each other, and can potentially provide insight into fundamental biological pathways that are perturbed when developmentally important genes are lost. In Project 2, we will leverage recent advances in 3D imaging, computer vision and machine-learning to make the morphological characterization of mouse mutants more accurate, quantitative, reproducible and accessible. Progeny from the same lines studied in Project 1 will be harvested at E15.5 and imaged using microCT scanning. We will then employ several different data analysis techniques to identify differences in the tissue volume and shapes in the mutant mice compared to synthetic image constructed from a pool of ‘normative’ samples. The goal of Project 3 is to use novel technologies in prospective cohorts of children with structural birth defects to identify genetic variation not ascertained by current methods. These “hidden” variants include structural rearrangements, as well as DNA mutations that arise post-zygotically and are not present in blood-derived DNA. We will use long-read based DNA and RNA sequencing methods, or deep short-read based DNA sequencing of multiple, non-blood derived tissues, on patients with structural birth defects whose clinical workup has been non-diagnostic.


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 = $1,603,958 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	5	4/15/2025	NON-COMPETING CONTINUATION	$160,393
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	5	12/18/2024	NON-COMPETING CONTINUATION	$1,443,565
														Subtotal = $1,603,958

Issue Date FY: 2024 ( Subtotal = $1,587,918 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	4	5/1/2024	NON-COMPETING CONTINUATION	$144,355
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	4	12/21/2023	NON-COMPETING CONTINUATION	$1,443,563
														Subtotal = $1,587,918

Issue Date FY: 2023 ( Subtotal = $1,990,925 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	002	3	9/8/2023	SUPPLEMENT FOR EXPANSION	$386,967
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	3	2/10/2023	NON-COMPETING CONTINUATION	$160,395
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	3	12/21/2022	NON-COMPETING CONTINUATION	$1,443,563
														Subtotal = $1,990,925

Issue Date FY: 2022 ( Subtotal = $1,603,958 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	2	12/15/2021	NON-COMPETING CONTINUATION	$1,443,565
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	2	5/2/2022	NON-COMPETING CONTINUATION	$160,393
														Subtotal = $1,603,958

Issue Date FY: 2021 ( Subtotal = $1,603,958 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	1	1/11/2021	NEW	$1,603,958
														Subtotal = $1,603,958

Grand Total All Awards = $8,390,717

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Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects

Award Number: P01HD104435

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/11/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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