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Oocyte polarity and BMP-mediated dorsoventral patterning

Award Number: R35GM131908
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: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Oocyte polarity and BMP-mediated dorsoventral patterning - Abstract: Bone Morphogenetic Protein (BMP) signaling directs the development of multiple organs and tissues, and is the cause of multiple congenital and adult diseases, including cardiovascular defects, kidney disease, pulmonary hypertension, and is important in medical applications in orthopedics, endodontics, and tissue engineering. BMP heterodimers exhibit consistently higher signaling activity to BMP homodimers in a multitude of contexts. Understanding how BMP heterodimers signal more effectively will lead to their more successful use in tissue engineering, bone repair, regeneration, and therapeutics. The zebrafish offers a paradigm of exclusive BMP heterodimer signaling in patterning the dorsoventral embryonic axis as a morphogen, with different levels specifying distinct cell types. This grant revealed specialized functions of the BMP Type I receptors in the heterodimer signaling mechanism, with Acvr1 exclusively providing the kinase activity to transduce the signal, whereas surprisingly the Bmpr1 kinase is dispensable. Intriguingly, Bmp2 homodimers were also found to require the heteromeric Type I receptor complex of Acvr1 and Bmpr1, indicating that the role of the heterodimer is to bring these two Type I receptors together, which elicits higher signaling activity than homomeric Type I signaling complexes. This proposal investigates the nature of the subfunctionalized roles of the Type I receptors in signaling and their trafficking in signal regulation through in vivo live imaging analysis, taking advantage of the large translucent zebrafish embryo. This grant demonstrated that the BMP gradient is interpreted into three cell fate domains by concentration thresholds of signaling and not by signal duration or gradient slope thresholds. Further studies are proposed to understand the outcomes of gradient thresholds and its regulation over time. In most vertebrates, polarity of the egg determines polarity of the embryo and establishes the embryonic dorsal-ventral axis and germ line. Egg polarity originates during oogenesis with the first polarized structure in vertebrate oocytes, the Balbiani body (Bb), a large, membrane-less structure conserved from insects to mammals typically composed of mitochondria and ribonucleoproteins, destined to the vegetal pole of the oocyte and egg. Although fundamental to forming the major axes of most vertebrate embryos, vertebrate oocyte polarity has been little studied. In zebrafish, a key factor Bucky ball (Buc) was discovered that establishes the Bb and oocyte polarity. Buc is a highly disordered protein that can undergo a phase transition to form amyloid-like fibers in vitro. The role of Buc in aggregating the Bb will be studied through unique buc hypomorphic alleles identified in the previous period that reveal its distinct functions in oocyte polarity, axis formation, and germ line development. From proteomics analysis of the Bb in the previous period, new highly disordered proteins with predicted self-aggregation domains will be studied in regulating the Bb. Importantly, inappropriate amyloid protein aggregates in cells are hallmarks of neurodegenerative disease. Thus, these studies are relevant to understanding how these aggregates form and can be dissociated in therapeutics.


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 = $712,070 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	8	5/5/2026	NON-COMPETING CONTINUATION	$712,070
														Subtotal = $712,070

Issue Date FY: 2025 ( Subtotal = $712,070 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	002	7	5/2/2025	NON-COMPETING CONTINUATION	$712,070
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	11/8/2024	COMPETING CONTINUATION	$0
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $712,070

Issue Date FY: 2024 ( Subtotal = $697,249 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	6	4/12/2024	COMPETING CONTINUATION	$769,179
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	3/7/2024	SUPPLEMENT FOR EXPANSION	-$71,930
														Subtotal = $697,249

Issue Date FY: 2023 ( Subtotal = $898,890 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	5/16/2023	NON-COMPETING CONTINUATION	$662,466
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	5/23/2023	SUPPLEMENT FOR EXPANSION	$236,424
														Subtotal = $898,890

Issue Date FY: 2022 ( Subtotal = $662,466 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	5/24/2022	NON-COMPETING CONTINUATION	$662,466
														Subtotal = $662,466

Issue Date FY: 2021 ( Subtotal = $662,466 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	5/25/2021	NON-COMPETING CONTINUATION	$662,466
														Subtotal = $662,466

Issue Date FY: 2020 ( Subtotal = $662,466 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	5/6/2020	NON-COMPETING CONTINUATION	$662,466
														Subtotal = $662,466

Issue Date FY: 2019 ( Subtotal = $613,126 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	4/10/2019	NEW	$613,126
														Subtotal = $613,126

Grand Total All Awards = $5,620,803

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Oocyte polarity and BMP-mediated dorsoventral patterning

Award Number: R35GM131908

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: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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