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Determining the role of E-cadherin and PAR-3 in epithelial symmetry breaking and repair

Award Number: R01DK144214
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Determining the role of E-cadherin and PAR-3 in epithelial symmetry breaking and repair - PROJECT SUMMARY/ABSTRACT Epithelial tissues encase metazoans, protecting them from and allowing regulated interaction with the environment. Essential to these functions is the establishment of an apical-basolateral polarity axis within cells and coordination of these axes across tissues, where apical surfaces face the environment, basolateral surfaces contact neighboring cells or substrates, and transmembrane junctions separate these domains and maintain intercellular adhesion. The emergence of a coordinated polarity axis in epithelial tissues is central to human health as failure in these processes can lead to tissue malfunctions, digestive diseases, embryonic lethality, or severe birth defects. Although some primordia that give rise to epithelia leverage structural asymmetries such as a basement membrane or naturally contact-free surface to direct apico-basolateral polarization, many epithelial tissues derive from unpolarized primordia and must generate polarity de novo. The molecular mechanisms underlying this epithelial symmetry breaking are poorly understood, especially in vivo, and have mostly been studied in cell culture models which do not replicate the developmental contexts in which symmetry breaking normally occurs. All epithelia tend to polarize the same molecular components, including the intracellular scaffolding protein PAR-3 which designates the apical surface and the transmembrane adhesion protein E-cadherin which comprises adherens junctions. These proteins commonly form clusters before localizing in this terminal configuration and, consistently, we found that PAR-3 and E- cadherin co-cluster into stereotyped ‘local polarity complexes’ (LPCs) at cell contacts to break symmetry within developing C. elegans intestinal epithelial cells. These LPCs then deliver polarity components to the future apical surface to define tissue-wide polarity. Thus, LPC formation and movement generate asymmetry at the cell and tissue-level in the C. elegans intestine and we will use state of the art genetic, proteomic, and imaging tools developed in my lab to determine how PAR-3 and E-cadherin enable this symmetry breaking. Aim 1 will determine the structure and composition of LPCs. Aim 2 will determine the molecular function of PAR-3 and E- cadherin, testing the hypothesis that PAR-3 modulates E-cadherin based adhesion and that this modulation within LPCs is required for polarity establishment. Aim 3 will leverage a new model for the repair of congenital epithelial defects, capitalizing on the discovery that PAR-3 can promote the repair of C. elegans cystic larval intestines while E-cadherin antagonizes this process. This system will serve as a companion system to embryonic intestinal polarization to determine the molecular interplay between PAR-3 and E-cadherin, adding an experimental framework to test the hypothesis that PAR-3 can modulate E-cadherin-based adhesion. These studies will reveal the mechanisms of epithelial symmetry breaking and thus are critical for our basic understanding of development and epithelial diseases such as polycystic kidney and microvillus inclusion disease and may also guide the repair congenital organ defects.


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 = $611,189 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/3/2026	NEW	$611,189
														Subtotal = $611,189

Grand Total All Awards = $611,189

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Determining the role of E-cadherin and PAR-3 in epithelial symmetry breaking and repair

Award Number: R01DK144214

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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