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The role of TTC7A in apical lumen formation and polarized trafficking in the intestinal epithelium

Award Number: F32DK130267
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The role of TTC7A in apical lumen formation and polarized trafficking in the intestinal epithelium - PROJECT SUMMARY The goal of this grant application is to understand how mutations in tetratricopeptide repeat domain 7a (TTC7A) affect formation of the polarized apical membrane; and how these mutations cause human disease. TTC7A loss of function mutations result in severe infantile-onset gastrointestinal disease, with phenotypes related to both gut epithelial and immune cell dysfunction. Previous studies suggest that loss of function in TTC7A results in altered apico-basolateral polarity and lumen formation in intestinal epithelial cells, although how this occurs remains unclear. Prevailing models suggest that initial organization of the apical membrane occurs at an initiation site (AMIS), which is enriched with distinct phosphoinositides compared to the basolateral membrane. The putative function of TTC7A is to serve as a chaperone and scaffolding protein for the phosphoinositide (PI) kinase – PI4KIIIα - at the plasma membrane. This kinase is principally responsible for the generation phosphoinositide PI4-phosphate (PI4P), which is one of the major precursors to the apically enriched PI(4,5P)2 and basolaterally enriched PI(3,4,5)P3. The role of PIs in specialized compartments is thought to partly direct vesicular cargo to the correct subcellular compartment – also responsible for proper polarity and lumenogenesis. Given the known function of TTC7A in coordinating PI4KIIIα localization, we hypothesize that TTC7A mutations perturb PI4KIIIαs normal functionality in cells, resulting in disordered spatiotemporal production of PI(4,5)P2 and PI(3,4,5)P3, thus driving improper cellular polarity, lumenogenesis and endosomal trafficking. To test this idea, we investigate the role of TTC7A in cell polarization, epithelial lumen formation, and endosomal trafficking. We propose studies using patient-derived enteroids, intestinal epithelial cell (Caco2) monolayers and Caco2 cyst cultures to determine the contribution of TTC7A to cell polarity and lumenogenesis. In Aim 1 of this proposal, we will further develop novel technology to monitor the formation of the early apical membrane, protein and lipid movement during apical membrane formation (and lumenogenesis), and how the proper subcellular localization of TTC7A contributes to these processes. We will carry out high resolution confocal and lightsheet imaging of phosphoinositide and apical and basolateral proteins localization in the polarization and lumen formation of Caco2- cysts and enteroids. In Aim 2 of this proposal we further translate our recently established high- throughput, quantitative endosomal trafficking assays for studies on primary patient derived enteroids. Further, we develop novel imaging to spatially probe endosomal trafficking in live enteroids. Our studies seek to identify if the membrane scaffolding function of TTC7A is important for correct spatial orientation of epithelial cells, and how the loss of TTC7A induces abnormal intestinal lumen formation. The results of these experiments may plausibly reveal general rules underlying epithelial development and suggest therapeutic approaches for TTC7A deficiency as well as other more common GI pathologies. Further, successful completion of these aims will provide extraordinary training towards my goal in becoming an epithelial biologist.


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 = $88,444 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/30/2024	NON-COMPETING CONTINUATION	$87,064
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/10/2025	NON-COMPETING CONTINUATION	$1,380
														Subtotal = $88,444

Issue Date FY: 2024 ( Subtotal = $84,592 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$78,972
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/29/2024	NON-COMPETING CONTINUATION	$5,620
														Subtotal = $84,592

Issue Date FY: 2022 ( Subtotal = $75,002 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/20/2022	NEW	$0
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/20/2022	NEW	$75,002
														Subtotal = $75,002

Grand Total All Awards = $248,038

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The role of TTC7A in apical lumen formation and polarized trafficking in the intestinal epithelium

Award Number: F32DK130267

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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