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Identifying novel regulators of the biogenesis and intracellular trafficking of ApoB lipoproteins

Award Number: F32GM144223
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Identifying novel regulators of the biogenesis and intracellular trafficking of ApoB lipoproteins - PROJECT SUMMARY - Metabolic syndrome affects up to 1/3 of the US population and is associated with dyslipidemia. In liver and intestine, lipid is catabolized, incorporated into complex lipids, stored in lipid droplets, or secreted as ApoB-containing lipoproteins (B-lps). Lipoprotein biogenesis plays a key role in governing cellular lipid flux in digestive organs; however, we have a poor understanding of the factors controlling B-lp capacity (size), secretion, and subcellular location(s) of lipidation. These knowledge gaps have been difficult to investigate due to the limitations of cell culture models for studying multi-organ phenomena and the relative inaccessibility of mammalian whole-animal models to visualize lipoprotein dynamics at the subcellular level. The zebrafish presents a unique solution to these challenges – in the embryonic and larval stages, the zebrafish robustly produces B-lps using genetically conserved pathways, is optically clear enabling imaging on the subcellular to whole-organism scale, and is amenable to genetic manipulation. In the developing larva, maternally deposited yolk lipid is packaged into B-lps by microsomal triglyceride transfer protein (MTP) in the yolk syncytial layer (YSL) and then secreted for distribution to other tissues. Larvae deficient in MTP inefficiently mobilize lipid resulting in abnormal lipid storage that reduces light transmission, giving the yolk sac a dark appearance that is easily identified by low-magnification light microscopy. Our lab was the first to characterize the B-lp biology of the “dark yolk” phenotype and has identified several genes with known and unknown roles in lipoprotein biogenesis. mia2/ctage5 mutants were recently found to exhibit the dark-yolk phenotype. The protein product of mia2/ctage5, Tango-like (TALI), may facilitate the formation of large diameter COPII vesicles to transport large B-lp cargos from the ER to the Golgi. I observe that B-lps in mia2/ctage5 deficient fish are almost exclusively small in diameter suggesting mia2/ctage5 plays a key role in regulating B-lp size. In aim 1, I will test the hypothesis that TALI preferentially interacts with large B-lps using transgenic zebrafish lines and a proximity labeling approach. Further, to test the hypothesis that mia2/ctage5 indirectly regulates B-lp size by modulating transcriptional pathways, I will monitor the transcriptome by RNAseq and by targeted analysis of lipid-related, COPII-dependent transcription factors. In aim 2, I will exploit the dark-yolk phenotype to uncover novel regulators of B-lp metabolism by conducting a forward genetic mutagenesis screen. Dark-yolk families will be characterized for defects in B-lp metabolism using transgenic ApoB reporter zebrafish and electron microscopy. High priority alleles will be mapped and further investigated for defects in lipid metabolism. By defining the role of mia2/ctage5 in regulating B-lp size and number and by identifying novel regulators of lipoprotein production, I will broaden our understanding of lipoprotein biogenesis and related pathologies. The experiments proposed, mutants discovered, training opportunities provided, and rigorous academic environment of the Farber Lab and Carnegie will support my long-term goal of becoming an independent investigator.


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 = $0 )
2025	2023	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	5/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2022	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	10/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	8/29/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$71,792
2023	2022	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	8/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $71,792

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	7/25/2022	NON-COMPETING CONTINUATION	$67,582
														Subtotal = $67,582

Issue Date FY: 2021 ( Subtotal = $65,994 )
2021	2021	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	7/6/2021	NEW	$65,994
2021	2021	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	1	7/6/2021	NEW	$0
														Subtotal = $65,994

Grand Total All Awards = $205,368

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Identifying novel regulators of the biogenesis and intracellular trafficking of ApoB lipoproteins

Award Number: F32GM144223

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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