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Structural Determinants of PIP2 Regulation

Award Number: R01HL059949
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Structural Determinants of PIP2 Regulation - Kir3 or GIRK (G protein gated inwardly rectifying K+) channels are activated by the vagus nerve to control heart rate. They are critical determinants of heart rate variability (HRV), an index of cardiac health, endowing the heart with the adaptability it needs to make rapid adjustments in heart rate. GIRK channels are attractive drug targets against atrial fibrillation (AF), the most common arrhythmia whose prevalence increases with age with an increased risk of mortality, stroke and myocardial infarction. The lack of specificity of the current antiarrhythmics used poses significant risk for ventricular side effects. This makes rather attractive targets expressed predominantly in the atria. Overactivity of cardiac GIRK channels has been implicated under the oxidative stress conditions characteristic of aging through a dysregulation of Protein Kinase C (PKC) enzymes, such as the increase in activity of the novel PKCe. Yet, even though full inhibitors of GIRK activity could reverse AF, they would also inhibit HRV, a side effect detrimental to cardiac health. Thus, the need for specific partial inhibitors that reverse the PKC-mediated channel activation but do not inhibit the vital functions of the channel is an unmet medical need. In this proposal, we investigate the mechanism by which PKC-dependent phosphorylation affects activity and show that it allosterically affects the interactions of the channel with PIP2, the master regulator of membrane protein function. We identify one phosphorylation site used by PKCe to stimulate channel activity and propose to determine all the sites involved and identify the gates they allosterically couple with to cause channel activation. In parallel, we have developed powerful structural computational models that allow us to test the action of small molecule inhibitors, which also allosterically control distinct channel gates via PIP2. In this proposal, we aim to set the stage in coupling the molecular insights of small molecule regulators of activity to specifically reverse the PKC-mediated overstimulation of channel activity. Our small molecule inhibitors will be tested in transgenic models of PKC-mediated AF with the goal to dial down the aberrant activity enough to correct the AF problem without compromising cardiac health.


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	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	26	2/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $733,308 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	27	5/14/2024	COMPETING CONTINUATION	$733,308
														Subtotal = $733,308

Issue Date FY: 2023 ( Subtotal = $718,816 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	26	5/19/2023	NON-COMPETING CONTINUATION	$718,816
														Subtotal = $718,816

Issue Date FY: 2022 ( Subtotal = $750,216 )
2022	2022	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	25	8/17/2022	NON-COMPETING CONTINUATION	$750,216
2022	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	24	2/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $750,216

Issue Date FY: 2021 ( Subtotal = $750,216 )
2021	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	24	7/29/2021	NON-COMPETING CONTINUATION	$750,216
2021	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	22	2/24/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $750,216

Issue Date FY: 2020 ( Subtotal = $773,265 )
2020	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	23	6/4/2020	COMPETING CONTINUATION	$773,265
														Subtotal = $773,265

Issue Date FY: 2019 ( Subtotal = $316,957 )
2019	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	22	4/12/2019	NON-COMPETING CONTINUATION	$316,957
														Subtotal = $316,957

Issue Date FY: 2018 ( Subtotal = $271,346 )
2018	2018	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	21	4/30/2018	NON-COMPETING CONTINUATION	$271,346
														Subtotal = $271,346

Issue Date FY: 2017 ( Subtotal = $281,534 )
2017	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	20	4/28/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$281,534
2017	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	002	20	6/2/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$118,139
2017	2016	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	19	6/2/2017	COMPETING CONTINUATION	-$118,139
														Subtotal = $281,534

Issue Date FY: 2016 ( Subtotal = $381,250 )
2016	2016	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	19	3/11/2016	COMPETING CONTINUATION	$381,250
2016	2015	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	18	3/10/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $381,250

Issue Date FY: 2015 ( Subtotal = $362,480 )
2015	2015	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	18	5/15/2015	NON-COMPETING CONTINUATION	$362,480
														Subtotal = $362,480

Issue Date FY: 2014 ( Subtotal = $414,288 )
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	17	7/16/2014	NON-COMPETING CONTINUATION	$414,288
														Subtotal = $414,288

Issue Date FY: 2013 ( Subtotal = $402,556 )
2013	2013	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	16	7/5/2013	NON-COMPETING CONTINUATION	$402,556
														Subtotal = $402,556

Issue Date FY: 2012 ( Subtotal = $410,799 )
2012	2012	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	15	5/1/2012	NON-COMPETING CONTINUATION	$368,331
2012	2012	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	15	9/6/2012	SUPPLEMENT FOR EXPANSION	$42,468
														Subtotal = $410,799

Issue Date FY: 2011 ( Subtotal = $368,437 )
2011	2011	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	14	4/15/2011	COMPETING CONTINUATION	$368,437
														Subtotal = $368,437

Issue Date FY: 2010 ( Subtotal = $286,755 )
2010	2010	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	13	4/26/2010	NON-COMPETING CONTINUATION	$286,755
														Subtotal = $286,755

Issue Date FY: 2009 ( Subtotal = $258,379 )
2009	2009	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	002	12	6/9/2009	NON-COMPETING CONTINUATION	$258,379
2009	2008	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	11	2/9/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$134,374
2009	2008	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	10	2/9/2009	NON-COMPETING CONTINUATION	-$134,374
														Subtotal = $258,379

Issue Date FY: 2008 ( Subtotal = $381,375 )
2008	2008	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cardiovascular Diseases Research	000	10	5/26/2008	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2007 ( Subtotal = $381,375 )
2007	2007	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cardiovascular Diseases Research	000	9	5/23/2007	COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2005 ( Subtotal = $339,000 )
2005	2005	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cardiovascular Diseases Research	000	8	5/5/2005	NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Issue Date FY: 2004 ( Subtotal = $339,000 )
2004	2004	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cardiovascular Diseases Research	000	7	3/26/2004	NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Grand Total All Awards = $10,711,997

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Structural Determinants of PIP2 Regulation

Award Number: R01HL059949

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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