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Characterization of mammalian COG complex-interacting Golgi trafficking machinery

Award Number: R01GM083144
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: 08/01/2008
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Characterization of mammalian COG complex-interacting Golgi trafficking machinery - PROJECT SUMMARY/ABSTRACT Intracellular membrane trafficking mediates the intracellular delivery of proteins and lipids. The process is bidirectional and consists of the anterograde (secretory) and retrograde (endocytic) branches. Intracellular membrane trafficking is evolutionary conserved, and its machinery is modular, with functionally homologous components operating on different trafficking steps. Therefore, a detailed understanding of one trafficking step will help in understanding the entire intracellular membrane trafficking process. The Conserved Oligomeric Golgi (COG) complex operates as a vesicular tether for intra-Golgi trafficking. The Golgi is the central hub for protein posttranslational modifications, mostly glycosylation. Consequently, the primary job of the COG is to tether vesicles that recycle resident enzymes and cargo receptors. To achieve its function, the COG interacts with SNAREs, Rabs, and other tethers, but the detailed understanding of these interactions is an enigma that we propose to solve by pairwise probing of COG/partner interactions, their kinetics, and by defining their molecular environment through proximity-labeling studies. Depletion of COG causes accumulation of specific transport intermediates – COG complex dependent (CCD) vesicles that are likely to represent a major class of Golgi vesicles that recycle Golgi enzymes and cargo receptors. Mutations in COG subunits result in congenital disorders of glycosylation (CDG) type II category, which belong to a group of autosomal recessive multi-systemic disorders with several distinguishable symptoms that include global developmental defects and microcephaly. These deficits are often accompanied by neurological and liver impairment. COG-CDG defects are studied in patients’ fibroblasts, which do not represent the most affected tissues; a more flexible cell base model will benefit our progress in developing a cure for this disorder. We hypothesize that a revealing of the molecular basis of COG/partner interactions will help in deciphering the mechanisms of assembly/disassembly of vesicle docking platforms and that a detailed analysis of different populations of CCD vesicles will uncover their specific origin, budding and tethering machinery and a complete set of proteins that traffic in a COG-dependent manner. The development of cell-based models for COG-CDGs will allow us to test the effects of different COG mutations without the need for patient involvement and pave the way for the development of treatment protocols. To test this hypothesis, first, we will characterize in molecular interactions between COG and its key partner proteins (Aim1). Next, we will use a degrone-assisted COG depletion to accumulate, purify and characterize CCD vesicles (Aim2). Finally, we will develop and characterize a novel iPSC-based cellular model for COG CDGs (Aim 3). Success in accomplishing these aims will provide a mechanistic understanding of COG complex function, characterize COG-dependent trafficking intermediates, and create a set of isogenic stem cell lines bearing human COG mutations. Moreover, these results will be necessary for a functional understanding of Golgi dynamic and vesicular trafficking in general.


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 = $409,543 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	16	3/31/2025	NON-COMPETING CONTINUATION	$409,543
														Subtotal = $409,543

Issue Date FY: 2024 ( Subtotal = $428,939 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	15	6/20/2024	NON-COMPETING CONTINUATION	$40,954
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	15	3/26/2024	NON-COMPETING CONTINUATION	$368,589
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	002	15	9/6/2024	SUPPLEMENT FOR EXPANSION	$19,396
2024	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	004	14	9/27/2024	COMPETING CONTINUATION	$28
2024	2021	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	003	13	9/27/2024	NON-COMPETING CONTINUATION	-$28
														Subtotal = $428,939

Issue Date FY: 2023 ( Subtotal = $409,543 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	14	3/21/2023	COMPETING CONTINUATION	$409,543
2023	2021	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	13	3/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,543

Issue Date FY: 2021 ( Subtotal = $398,865 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	13	4/14/2021	NON-COMPETING CONTINUATION	$398,865
														Subtotal = $398,865

Issue Date FY: 2020 ( Subtotal = $398,437 )
2020	2020	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	12	3/31/2020	NON-COMPETING CONTINUATION	$398,437
														Subtotal = $398,437

Issue Date FY: 2019 ( Subtotal = $456,329 )
2019	2019	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	002	11	4/24/2019	NON-COMPETING CONTINUATION	$395,862
2019	2019	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	003	11	8/22/2019	SUPPLEMENT FOR EXPANSION	$60,467
2019	2018	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	10	3/11/2019	COMPETING CONTINUATION	$2,734
2019	2017	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	9	3/11/2019	NON-COMPETING CONTINUATION	-$2,734
														Subtotal = $456,329

Issue Date FY: 2018 ( Subtotal = $506,046 )
2018	2018	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	10	7/26/2018	COMPETING CONTINUATION	$393,717
2018	2018	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	002	10	9/17/2018	SUPPLEMENT FOR EXPANSION	$112,329
2018	2017	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	9	7/30/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $506,046

Issue Date FY: 2017 ( Subtotal = $365,244 )
2017	2017	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	9	11/22/2016	NON-COMPETING CONTINUATION	$328,719
2017	2017	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	9	8/15/2017	NON-COMPETING CONTINUATION	$36,525
														Subtotal = $365,244

Issue Date FY: 2016 ( Subtotal = $365,244 )
2016	2016	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	8	4/6/2016	NON-COMPETING CONTINUATION	$36,525
2016	2016	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	8	11/9/2015	NON-COMPETING CONTINUATION	$328,719
														Subtotal = $365,244

Issue Date FY: 2015 ( Subtotal = $562,954 )
2015	2015	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	002	7	9/8/2015	SUPPLEMENT FOR EXPANSION	$197,710
2015	2015	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	7	2/9/2015	NON-COMPETING CONTINUATION	$36,525
2015	2015	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	7	11/18/2014	NON-COMPETING CONTINUATION	$328,719
														Subtotal = $562,954

Issue Date FY: 2014 ( Subtotal = $365,244 )
2014	2014	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	6	12/23/2013	COMPETING CONTINUATION	$365,244
														Subtotal = $365,244

Issue Date FY: 2012 ( Subtotal = $357,980 )
2012	2012	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	5	5/17/2012	NON-COMPETING CONTINUATION	$357,980
														Subtotal = $357,980

Issue Date FY: 2011 ( Subtotal = $324,492 )
2011	2011	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	4	6/3/2011	NON-COMPETING CONTINUATION	$225,267
2011	2011	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	001	4	8/26/2011	SUPPLEMENT FOR EXPANSION	$99,225
														Subtotal = $324,492

Issue Date FY: 2010 ( Subtotal = $227,542 )
2010	2010	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	3	5/19/2010	NON-COMPETING CONTINUATION	$227,542
														Subtotal = $227,542

Issue Date FY: 2009 ( Subtotal = $229,840 )
2009	2009	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	2	6/5/2009	NON-COMPETING CONTINUATION	$229,840
														Subtotal = $229,840

Issue Date FY: 2008 ( Subtotal = $269,840 )
2008	2008	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Biomedical Research and Research Training	000	1	7/17/2008	NEW	$269,840
														Subtotal = $269,840

Grand Total All Awards = $6,076,082

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Characterization of mammalian COG complex-interacting Golgi trafficking machinery

Award Number: R01GM083144

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: 08/01/2008

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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