Monday, August 18, 2025 8/18/2025

Molecular basis of ILK-mediated cell adhesion

Award Number: R01HL058758
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/1999
PERIOD OF PERFORMANCE END DATE: 03/31/2028

Group Awards By:

View Award Description

Molecular basis of ILK-mediated cell adhesion - The long term goal of this renewal proposal is to gain deep mechanistic understanding of integrin-mediated cell adhesion that occurs in virtually every human life process. Integrins are a family of 24 heterodimeric (α/β) transmembrane receptors differentially expressed in cells and tissues. Being expressed in inactive form, integrins are activated via a distinct process called “inside-out” signaling where cellular stimulation elicits intracellular signals to induce global conformational change of the receptors to bind extracellular matrix (ECM) ligands. However, for cells to firmly adhere to ECM, or change shape, or migrate as required by many physiological processes, the activated integrins need to further communicate with intracellular cytoskeleton (“outside-in” signaling) via the formation of large protein complexes called focal adhesions (FAs). Understanding the mechanism of such bi-directional signaling phenomenon has been the central topic of cell adhesion biology ever since the discovery of integrins in middle 1980s. While much has been learned about the integrin “inside-out” signaling, how FAs are assembled to mediate the integrin “outside-in” signaling still remains highly elusive due to its complex and dynamic nature. To this end, we have been focusing on integrin-linked kinase (ILK) - a major FA regulator and initiator of the integrin outside-in signaling. ILK was long thought to function as a Ser/Thr kinase to phosphorylate integrin β cytoplasmic tail (CT) to trigger signaling. However, our recent studies challenged the longstanding dogma by showing that ILK is a non-catalytic pseudokinase yet can transmit mechanical signaling linking integrin to actin to regulate cytoskeleton reorganization and cell adhesion. Interestingly, ILK was also shown to mediate multiple important biochemical signaling events yet much of the published data were misinterpreted by considering ILK as a kinase with exact mechanisms being unknown. This proposal will rigorously address this issue with a central hypothesis that an ILK-centered heterotrimer called IPP spatiotemporally recruits distinct signaling enzymes to integrin adhesion sites and trigger signaling. In Aim1 we will investigate a longstanding puzzle of ILK-mediated Ser/Thr kinase AKT1 signaling. Aim2 will elucidate the mechanism of ILK-mediated small GTPase Rac1 signaling. Aim3 will develop potent ILK inhibitor that targets at the pseudoactive site of ILK to regulate the IPP stability, which will help to deepen the understanding of the ILK signaling events. Overall, our proposed studies reflect a strong momentum of our program towards establishing a new paradigm of how ILK acts as a multi-functional pseudokinase to spatiotemporally regulate integrin outside- in signaling events to promote dynamic cell adhesion and diverse adhesion-dependent physiological processes. These studies, along with the development of potent ILK inhibitor, may also transform the diagnosis and treatment of ILK-associated diseases such as heart failure and cancer.


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 = $550,409 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	002	24	3/20/2025	NON-COMPETING CONTINUATION	$495,369
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	003	24	8/4/2025	NON-COMPETING CONTINUATION	$55,040
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	23	3/18/2025	COMPETING CONTINUATION	$2,346
2025	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	22	3/18/2025	NON-COMPETING CONTINUATION	-$2,346
														Subtotal = $550,409

Issue Date FY: 2024 ( Subtotal = $550,409 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	23	3/1/2024	COMPETING CONTINUATION	$495,370
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	23	6/27/2024	COMPETING CONTINUATION	$55,039
														Subtotal = $550,409

Issue Date FY: 2022 ( Subtotal = $402,500 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	22	3/10/2022	NON-COMPETING CONTINUATION	$362,250
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	22	6/18/2022	NON-COMPETING CONTINUATION	$40,250
														Subtotal = $402,500

Issue Date FY: 2021 ( Subtotal = $402,500 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	21	3/19/2021	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2020 ( Subtotal = $401,875 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	20	3/23/2020	NON-COMPETING CONTINUATION	$401,875
														Subtotal = $401,875

Issue Date FY: 2019 ( Subtotal = $400,000 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	19	3/29/2019	COMPETING CONTINUATION	$400,000
2019	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	18	3/28/2019	NON-COMPETING CONTINUATION	$0
2019	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	002	18	7/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $400,000

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	003	18	5/30/2017	NON-COMPETING CONTINUATION	$396,250
2017	2016	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	17	10/28/2016	EXTENSION WITH OR WITHOUT FUNDS	$20,921
2017	2015	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	16	10/28/2016	NON-COMPETING CONTINUATION	-$20,921
2017	2012	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	002	13	5/8/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $396,250

Issue Date FY: 2016 ( Subtotal = $396,250 )
2016	2016	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	17	6/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$396,250
														Subtotal = $396,250

Issue Date FY: 2015 ( Subtotal = $390,306 )
2015	2015	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	16	6/9/2015	NON-COMPETING CONTINUATION	$390,306
														Subtotal = $390,306

Issue Date FY: 2014 ( Subtotal = $388,325 )
2014	2014	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	15	5/16/2014	NON-COMPETING CONTINUATION	$388,325
														Subtotal = $388,325

Issue Date FY: 2013 ( Subtotal = $377,230 )
2013	2013	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	14	8/1/2013	COMPETING CONTINUATION	$377,230
2013	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	13	7/30/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,230

Issue Date FY: 2012 ( Subtotal = $388,575 )
2012	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	13	3/26/2012	NON-COMPETING CONTINUATION	$388,575
														Subtotal = $388,575

Issue Date FY: 2011 ( Subtotal = $392,500 )
2011	2011	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	12	3/3/2011	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2010 ( Subtotal = $392,500 )
2010	2010	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	000	11	3/17/2010	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2009 ( Subtotal = $392,500 )
2009	2009	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cardiovascular Diseases Research	001	10	4/14/2009	COMPETING CONTINUATION	$392,500
2009	2007	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	9	4/14/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2007 ( Subtotal = $290,143 )
2007	2007	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	9	3/7/2007	NON-COMPETING CONTINUATION	$290,143
														Subtotal = $290,143

Issue Date FY: 2006 ( Subtotal = $298,809 )
2006	2006	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	8	2/22/2006	NON-COMPETING CONTINUATION	$298,809
														Subtotal = $298,809

Issue Date FY: 2005 ( Subtotal = $306,000 )
2005	2005	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	7	2/16/2005	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Issue Date FY: 2004 ( Subtotal = $306,000 )
2004	2004	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	6	4/5/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$306,000
														Subtotal = $306,000

Grand Total All Awards = $8,726,016

Page 1 of 2 (60 items)12

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Molecular basis of ILK-mediated cell adhesion

Award Number: R01HL058758

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/1999

PERIOD OF PERFORMANCE END DATE: 03/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer