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The Role of the Adaptor Protein Enkurin in Left-Right Patterning- a Promising Link Between Polycystin-2 and Calcium Signaling

Award Number: F31GM155995
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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The Role of the Adaptor Protein Enkurin in Left-Right Patterning- a Promising Link Between Polycystin-2 and Calcium Signaling - Project Summary Defects in left-right (LR) patterning underlie some of the most severe congenital heart defects (CHDs), which can be fatal if not surgically corrected. However, we still do not have a complete understanding of the genes and cell signaling pathways that are used to pattern the LR body axis, which severely limits our ability to identify genetic risk factors for CHDs. In fish, frogs, mice, and humans, LR patterning is initiated within ciliated structures known as left-right organizers (LROs). Motile cilia within these LROs rotate and generate a leftward fluid flow that is proposed to be mechanically sensed by a cation channel complex in the cilium composed of Polycsytin-2 (Pkd2) and Polycystin 1-Like-1 (Pkd1L1). In response to flow, this channel complex would generate a calcium gradient on the left side of KV. The resulting signaling pathway ultimately culminates in the downregulation of the Transforming Growth Factor Beta (TGF-β) inhibitor dand5 mRNA on the left side of Kupffer’s Vesicle (KV)- the zebrafish LRO. However, the downstream effectors of fluid flow that link the channel and calcium signaling to the downregulating of dand5, are unknown. My preliminary work identified Enkurin as highly expressed in KV. Past published work on Enkurin has shown that Enkurin binds to Transient receptor potential channel (TRPC) cation channels to physically link them calcium signaling effectors in mouse sperm. As Pkd2 is in the same TRP family with these TRPC channels, I hypothesize Enkurin binds Pkd2 and links it to downstream calcium signaling machinery in KV, which is required to regulate dand5 mRNA. To test this hypothesis, I will characterize an enkurin mutant to determine how LR patterning and Calmodulin signaling is affected in KV (aim 1). I will determine where Enkurin localizes subcellularly, assess for changes in subcellular localization in response to fluid flow, and test for colocalization with Pkd2 and Calmodulin (aim 2). I will explore the Enkurin interactome directly testing the binding of Enkurin to Pkd2 and Calmodulin. I will also use TurboID as an unbiased approach to characterize Enkurin’s interactome and identify additional binding partners (aim 3). This project will fill a significant knowledge gap in identifying the proteins and processes downstream of cilia that regulate LR patterning. Importantly, this work has the potential to directly link Pkd2 to downstream calcium signaling for the first time. This project will also identify new binding partners of Enkurin, which could be playing key roles in LR patterning, and thus identify previously unappreciated risk factors for CHDs. This project will also advance my skills in protein biochemistry, developmental biology, and imaging techniques, and the supportive and collaborative nature of Princeton’s Department of Molecular Biology and the Burdine lab will further support my scientific development.


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 = $37,102 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	2	1/9/2026	NON-COMPETING CONTINUATION	$36,538
2026	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	1/8/2026	NEW	$564
														Subtotal = $37,102

Issue Date FY: 2025 ( Subtotal = $35,974 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	1	12/19/2024	NEW	$0
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	12/1/2024	NEW	$35,974
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	1	12/19/2024	NEW	$0
														Subtotal = $35,974

Grand Total All Awards = $73,076

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The Role of the Adaptor Protein Enkurin in Left-Right Patterning- a Promising Link Between Polycystin-2 and Calcium Signaling

Award Number: F31GM155995

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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