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Polycystins, cilia, and extracellular vesicles in C. elegans

Award Number: R01DK059418
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Polycystins, cilia, and extracellular vesicles in C. elegans - Project Summary Autosomal dominant polycystic kidney disease (ADPKD) is a common, life threatening disease that affects 1/400-1/1000. ADPKD is caused by mutations in PKD1 and PKD2, which encode polycystin-1 and polycystin-2 (PC1 and PC2). Remarkably, the function of the polycystins remains enigmatic almost 30 years after their cloning and 20 years after their discovery on renal primary cilia. Besides cilia, PC1 and PC2 are also found in other subcellular locations including extracellular vesicles (EVs). Urinary EVs can be used as biomarkers of renal disease including ADPKD. Whether these polycystin-carrying EVs are of ciliary origin and what role EVs play in healthy and diseased kidneys remains unknown. In the model organism C. elegans and mammals, the polycystins LOV-1/PC1 and PKD-2/PC2 are architecturally similar, act in the same genetic pathway, function in a sensory capacity, localize to primary/sensory cilia, and are shed in EVs, suggesting ancient conservation. We will use our established C. elegans model and fluorescently labeled ciliary EV cargoes PC1 (LOV-1) and PC2 (PKD-2) to study ciliary EV shedding, bioactivity, and targeting in living animals. Super resolution, real time imaging reveals that LOV-1 and PKD-2 co-localize on ciliary EVs and that cilia shed polycystin-carrying EVs from two distinct sites - the ciliary tip and the ciliary base. Ciliary tip EVs shedding is triggered by mechanical stimulation and functions in animal-to-animal communication. For example, males deposit PKD-2-carrying EVs onto the vulva of the hermaphrodite during mating. We also used PKD-2::GFP to enrich and profile the C. elegans EV proteome, and, more specifically, the polycystin EV signalosome. We hypothesize that polycystin-carrying EVs act as discrete signaling units and carry specific cargo for biogenesis, cargo sorting, signaling, and targeting. In Aim 1, we will define the relationships between polycystins and the components of polycystin- carrying EVs. In Aim 2, we will ascertain the function of polycystin-associated EV cargo and test the hypotheses that the polycystins and associated proteins function as a signalosome in ciliary EVs and in ciliated sensory neurons. In Aim 3, we focus on EV function in health and disease by studying PKD1 and PKD2 pathogenic mutations and variants of uncertain significance in our C. elegans model. This competing renewal application will uncover the fundamentals of ciliary EV biology and the functions of the polycystins on cilia and EVs. Our studies will provide insight about the biology of normal and pathological processes that require or are modulated by EVs including ciliopathies.


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	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	25	4/29/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	2/19/2025	COMPETING CONTINUATION	$45,382
2025	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	2/19/2025	NON-COMPETING CONTINUATION	-$45,382
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $690,019 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	8/22/2024	NON-COMPETING CONTINUATION	$569,032
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	25	8/28/2024	SUPPLEMENT FOR EXPANSION	$120,987
														Subtotal = $690,019

Issue Date FY: 2023 ( Subtotal = $592,743 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	4/11/2023	COMPETING CONTINUATION	$592,743
														Subtotal = $592,743

Issue Date FY: 2022 ( Subtotal = $235,500 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	23	7/26/2022	NON-COMPETING CONTINUATION	$235,500
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	11/3/2021	COMPETING CONTINUATION	$45,382
2022	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	11/3/2021	NON-COMPETING CONTINUATION	-$45,382
														Subtotal = $235,500

Issue Date FY: 2021 ( Subtotal = $235,500 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	6/11/2021	NON-COMPETING CONTINUATION	$235,500
														Subtotal = $235,500

Issue Date FY: 2020 ( Subtotal = $234,250 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	7/30/2020	COMPETING CONTINUATION	$234,250
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	7/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $234,250

Issue Date FY: 2019 ( Subtotal = $372,116 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	5/15/2019	NON-COMPETING CONTINUATION	$372,116
														Subtotal = $372,116

Issue Date FY: 2018 ( Subtotal = $443,674 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	6/21/2018	NON-COMPETING CONTINUATION	$443,674
														Subtotal = $443,674

Issue Date FY: 2017 ( Subtotal = $443,674 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/29/2017	NON-COMPETING CONTINUATION	$372,116
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	9/11/2017	SUPPLEMENT FOR EXPANSION	$71,558
														Subtotal = $443,674

Issue Date FY: 2016 ( Subtotal = $372,116 )
2016	2016	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	6/30/2016	NON-COMPETING CONTINUATION	$372,116
														Subtotal = $372,116

Issue Date FY: 2015 ( Subtotal = $372,116 )
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	8/17/2015	COMPETING CONTINUATION	$372,116
														Subtotal = $372,116

Issue Date FY: 2014 ( Subtotal = $389,434 )
2014	2014	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/28/2014	NON-COMPETING CONTINUATION	$323,475
2014	2014	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	4/9/2014	SUPPLEMENT FOR EXPANSION	$65,959
														Subtotal = $389,434

Issue Date FY: 2013 ( Subtotal = $312,925 )
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/14/2013	NON-COMPETING CONTINUATION	$291,846
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	5/14/2013	NON-COMPETING CONTINUATION	$21,079
														Subtotal = $312,925

Issue Date FY: 2012 ( Subtotal = $325,081 )
2012	2012	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	5/2/2012	NON-COMPETING CONTINUATION	$325,081
														Subtotal = $325,081

Issue Date FY: 2011 ( Subtotal = $372,639 )
2011	2011	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	8/18/2011	COMPETING CONTINUATION	$372,639
														Subtotal = $372,639

Issue Date FY: 2010 ( Subtotal = $355,224 )
2010	2010	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/16/2010	NON-COMPETING CONTINUATION	$355,224
2010	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	7/16/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $355,224

Issue Date FY: 2009 ( Subtotal = $462,621 )
2009	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	004	10	9/17/2009	SUPPLEMENT FOR EXPANSION	$111,099
2009	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	10	7/31/2009	SUPPLEMENT FOR EXPANSION	$50,133
2009	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	7/30/2009	NON-COMPETING CONTINUATION	$301,389
2009	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	8	1/26/2009	NON-COMPETING CONTINUATION	-$284,996
2009	2008	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	1/26/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$284,996
														Subtotal = $462,621

Issue Date FY: 2008 ( Subtotal = $284,996 )
2008	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	8	6/23/2008	NON-COMPETING CONTINUATION	$284,996
														Subtotal = $284,996

Grand Total All Awards = $8,590,660

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Polycystins, cilia, and extracellular vesicles in C. elegans

Award Number: R01DK059418

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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