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Nuclear Events in PTHR1 Action on Bone

Award Number: R01DK047420
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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Parathyroid hormone (PTH) is an essential regulator of calcium homeostasis and became the prototypic osteoanabolic hormone for treating osteoporosis. On the other hand, hyperparathyroidism, with its consequent bone breakdown, is a major problem in and of itself and in chronic renal failure. The hormone acts through its G-protein-coupled receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. To do this, the osteoblast produces receptor activator of nuclear factor kappa-β ligand (RANKL) in response to PTH. RANKL is widely considered a principal mediator of PTH-induced bone catabolism and has been associated with bone loss in hyperparathyroidism. Our work in the last cycle of this grant revealed that PTH activates cAMP/protein kinase A (PKA) to inhibit salt-inducible kinases (SIKs) and requires protein phosphatases (PPs) to stimulate Rankl expression in osteoblasts. Knockdown of salt-inducible kinases (SIKs) 2 and 3 and cAMP- regulated transcription coactivators 2 and 3 (CRTC2 and 3) indicate that all four are part of this pathway. Moreover, inhibition of serine-threonine protein phosphatases decreased both PTH-induced Rankl expression and the stimulation by PTH(1-34) of CRTC2 and 3 translocation into the nucleus. Upon entry into the nucleus, these CRTCs associate with unknown basic leucine zipper domain (bZip) transcription factor(s), activating Rankl transcription through binding to its distal PTH-responsive cAMP-response elements (CREs). From these data of cells in culture and preliminary data in vivo, we have developed the central hypothesis that SIK/PP regulation of CRTC2/3 is essential to their function in the skeleton, and PTH controls this regulation. The long- term goals of this work are to delineate the signaling and transcriptional regulatory mechanisms conveying PTH action in bone. Consequently, the specific aims to test our hypothesis of this resubmitted competing renewal proposal focus on the SIK and PP regulation of CRTC2/3 function and action on Rankl, and will, 1) determine the mechanism of PTH regulation of Rankl transcription in osteoblasts by a. elucidating the regulatory mechanisms involved in CRTC2/3 nuclear translocation in osteoblasts, b. identifying the bZip transcription factor(s) responsible for CRTC2/3-induced Rankl transcription, 2) determine the role of CRTC2/3 in bone development and PTH’s anabolic and catabolic effects by a. determining the site and role of osteoblast CRTC2/3 in bone development, b. ascertaining the effects of deletion of CRTC2/3 on PTH’s anabolic and catabolic actions in bones of adult mice. The results of this work will make major contributions to our knowledge of how PTH exerts its nuclear effects on skeletal function through the SIK/PP/CRTC/bZip pathway. In so doing, the data will also provide new perspectives into treatment of disorders of calcium metabolism and other severe diseases functioning through the PTHR1 pathway such as Jansen’s metaphyseal chondrodysplasia and McCune-Albright syndrome.


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 = -$9,599 )
2025	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	30	11/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,800
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	11/19/2024	NON-COMPETING CONTINUATION	-$386,399
														Subtotal = -$9,599

Issue Date FY: 2024 ( Subtotal = $386,400 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	6/14/2024	NON-COMPETING CONTINUATION	$386,400
														Subtotal = $386,400

Issue Date FY: 2023 ( Subtotal = $494,282 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	5/31/2023	NON-COMPETING CONTINUATION	$402,083
2023	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	5/9/2023	COMPETING CONTINUATION	$92,199
														Subtotal = $494,282

Issue Date FY: 2022 ( Subtotal = $400,834 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	4/26/2022	COMPETING CONTINUATION	$400,834
														Subtotal = $400,834

Issue Date FY: 2021 ( Subtotal = -$244,067 )
2021	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	26	8/27/2021	NON-COMPETING CONTINUATION	-$244,067
2021	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	3/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = -$244,067

Issue Date FY: 2020 ( Subtotal = $389,874 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	3/17/2020	NON-COMPETING CONTINUATION	$389,874
														Subtotal = $389,874

Issue Date FY: 2019 ( Subtotal = $389,874 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	4/12/2019	NON-COMPETING CONTINUATION	$389,874
														Subtotal = $389,874

Issue Date FY: 2018 ( Subtotal = $464,154 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	4/23/2018	NON-COMPETING CONTINUATION	$464,154
														Subtotal = $464,154

Issue Date FY: 2017 ( Subtotal = $437,142 )
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	6/19/2017	NON-COMPETING CONTINUATION	$38,988
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	3/31/2017	NON-COMPETING CONTINUATION	$350,886
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	23	9/14/2017	SUPPLEMENT FOR EXPANSION	$47,268
														Subtotal = $437,142

Issue Date FY: 2016 ( Subtotal = $389,874 )
2016	2016	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	4/1/2016	COMPETING CONTINUATION	$392,138
2016	2016	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	4/6/2016	COMPETING CONTINUATION	-$2,264
														Subtotal = $389,874

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	9/10/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $334,950 )
2014	2014	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	3/21/2014	NON-COMPETING CONTINUATION	$334,950
														Subtotal = $334,950

Issue Date FY: 2013 ( Subtotal = $323,228 )
2013	2013	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	5/20/2013	NON-COMPETING CONTINUATION	$21,773
2013	2013	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	3/14/2013	NON-COMPETING CONTINUATION	$301,455
														Subtotal = $323,228

Issue Date FY: 2012 ( Subtotal = $334,950 )
2012	2012	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	2/14/2012	NON-COMPETING CONTINUATION	$334,950
														Subtotal = $334,950

Issue Date FY: 2011 ( Subtotal = $385,000 )
2011	2011	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	6/6/2011	COMPETING CONTINUATION	$50,050
2011	2011	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/25/2011	COMPETING CONTINUATION	$334,950
														Subtotal = $385,000

Issue Date FY: 2010 ( Subtotal = $85,436 )
2010	2010	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Trans-NIH Recovery Act Research Support	006	17	4/23/2010	SUPPLEMENT FOR EXPANSION	-$57,000
2010	2010	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Trans-NIH Recovery Act Research Support	007	17	5/19/2010	SUPPLEMENT FOR EXPANSION	$57,000
2010	2010	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Trans-NIH Recovery Act Research Support	005	17	4/7/2010	SUPPLEMENT FOR EXPANSION	$57,000
2010	2009	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	17	12/10/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,782
2010	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	11/6/2009	NON-COMPETING CONTINUATION	-$50,255
2010	2009	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	11/10/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,770
2010	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	16	12/10/2009	NON-COMPETING CONTINUATION	$6,848
2010	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	12/10/2009	NON-COMPETING CONTINUATION	$28,855
														Subtotal = $85,436

Issue Date FY: 2009 ( Subtotal = $319,506 ) (Continued on the next page)
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	1/12/2009	NON-COMPETING CONTINUATION	$259,688
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	002	16	6/18/2009	SUPPLEMENT FOR EXPANSION	$30,963
Grand Total All Awards = $7,487,468

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Nuclear Events in PTHR1 Action on Bone

Award Number: R01DK047420

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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