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Optical dissection of human embryonic germ layer patterning mechanisms using microengineered stem cell models

Award Number: R01HD108803
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Optical dissection of human embryonic germ layer patterning mechanisms using microengineered stem cell models - Project Summary In the first two weeks of development, the human embryo breaks symmetry twice, transforming itself from a uniform ball of cells into a highly-patterned, spatially organized set of tissues. Although decades of elegant genetics and biochemistry in non-human model organisms have uncovered many of the essential signaling proteins and pathways for embryonic patterning at this early stage, a lack of tools for directly manipulating the signaling in time and space, as well as limitations to working with human embryos, have limited our ability to understand how these early patterning events arise in humans. Thus, my laboratory seeks to develop engineering strategies to (1) understand what patterns of signaling activity encode extracellular information, and (2) determine how these patterns are decoded at the tissue level to drive high fidelity collective cell fate decisions in human embryonic stem cells. This proposal brings together many recent advances in stem cell and molecular engineering to decode how spatiotemporal signaling and embryo size instruct tissue fate patterning. We leverage advances in 2D micropatterning, 3D bioprinting, cellular optogenetic control over developmental signaling pathways, and CRISPR-based reporters of cell signaling pathways. Together, these technologies give us unprecedented control over and visualization of microengineered models of human gastrulation, thereby enabling us to investigate the principles of environmental information transmission and potential mechanisms of pregnancy loss and developmental anomalies that arise with a surprisingly high frequency (10-20% by some estimates) in the early human embryo. In addition, our platform does not face the same ethical barriers that have limited human embryo research, allowing us to ascertain how physical and information-bearing parameters of the embryo lead to stereotyped patterning of the germ layers during human gastrulation. In this proposal, we focus on the role of canonical developmental signaling pathways by dissecting the effects of spatiotemporal signaling and variance of the Wnt pathway on germ layer fate positioning in 2D (Aim 1); examining the role of Erk signaling on positioning, dynamics, and coordination of cells during the development of the mesoderm/trophectoderm boundary (Aim 2); and examining the effect of cell number and tissue size in 3D gastrulating models of the human epiblast and amniotic sac (Aim 3).


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 = $313,029 )
2025	2025	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Child Health and Human Development Extramural Research	000	4	4/4/2025	NON-COMPETING CONTINUATION	$313,029
														Subtotal = $313,029

Issue Date FY: 2024 ( Subtotal = $310,799 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Child Health and Human Development Extramural Research	000	3	4/30/2024	NON-COMPETING CONTINUATION	$310,799
														Subtotal = $310,799

Issue Date FY: 2023 ( Subtotal = $314,802 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Child Health and Human Development Extramural Research	000	2	3/15/2023	NON-COMPETING CONTINUATION	$314,802
														Subtotal = $314,802

Issue Date FY: 2022 ( Subtotal = $315,688 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Child Health and Human Development Extramural Research	000	1	6/15/2022	NEW	$315,688
														Subtotal = $315,688

Grand Total All Awards = $1,254,318

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Optical dissection of human embryonic germ layer patterning mechanisms using microengineered stem cell models

Award Number: R01HD108803

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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