Saturday, September 20, 2025 9/20/2025

Novel role of integrins in paracrine regulation of vasculature

Award Number: R01HL071625
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/14/2003
PERIOD OF PERFORMANCE END DATE: 06/30/2024

Group Awards By:

View Award Description

Novel role of integrins in paracrine regulation of vasculature - Abstract. This proposal aims to understand the nature of the crosstalk between vascular and resident innate immune cells (microglia) in order to normalize dysfunctional (insufficient or excessive) vasculature and to develop novel tissue regeneration and revascularization technologies. It addresses the basic functions of microglia, which plays a coordinating role in numerous pathologies from developmental abnormalities and behavioral problems to neurodegenerative disorders to neuropathology of HIV. Using microglia-specific Kindlin3 and integrin knockouts, we show that despite the normal presence in brain and retinas, Kindlin deficient microglia is characterized by deregulated production of angiogenic factors. As a result, retinal vasculature in microglia-specific KOs has abnormally dense and irregular vascular pattern and exhibits excessive growth of blood vessels into the normally avascular area of photoreceptors. We show that this is mediated by overproduction of TGFβ1 by K3KO microglia, since knockout of microglial TGFβ1 in K3KO mice rescues this vascular phenotype. Mechanistically, while normal microglia “switches off” its production of TGFβ1 in matrix with higher ligand density or higher stiffness, this mechano-switch is abrogated in Kindlin3 deficient microglia. We show that the mechanosensory function of microglia depends on the membrane-to-cortex attachment (MCA) complex, which is disrupted by the lack of Kindlin3. We demonstrate that Kindlin3 binds not only to integrin, to plasma membrane but also connects to cytoskeleton (by direct binding to leupaxin/paxillin) and disruption of K3-paxillin binding disrupts MCA complex. These results led us to formulate a novel paradigm-changing hypothesis that: Kindlin3 coordinates MCA complex, which, in turn, orchestrates the mechanosensory function of microglia, i.e. its ability to respond to the mechanical properties of ECM by the changes in angiogenic factors expression. The mechanistic question: “How exactly microglia is able to sense the ECM properties in order to regulate vasculature?” will be answered in this proposal. Aim 1. To test the hypothesis that paracrine regulation of angiogenesis is controlled by β1 rather than β2 integrin on microglia and requires a fully functional complex between integrin and Kindlin3, which, in turn, regulates microglial expression of TGFβ. Aim 2. To test a hypothesis that integrin-kindlin3-leupaxin/paxillin complex functions as a sensor of membrane tension and as a result, ECM composition and mechanical properties and to define the structure-functional determinants of this complex. We will utilize our recently developed 3D hydrogel-based system with controlled mechanical characteristics (ligand density, stiffness and a relaxation time). Our new in vitro technologies will lead to the development of novel materials and approaches for tissue regeneration and microglia-controlled revascularization. The knowledge of microglia will lead to new treatments for multiple sclerosis, Alzheimer's disease and other neuro- and retinal pathologies.


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 = -$118,109 )
2025	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	17	11/23/2024	NON-COMPETING CONTINUATION	-$118,109
														Subtotal = -$118,109

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	17	8/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $617,218 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	17	6/17/2021	NON-COMPETING CONTINUATION	$617,218
														Subtotal = $617,218

Issue Date FY: 2020 ( Subtotal = $617,218 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	16	6/22/2020	NON-COMPETING CONTINUATION	$617,218
														Subtotal = $617,218

Issue Date FY: 2019 ( Subtotal = $613,384 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	002	15	6/25/2019	NON-COMPETING CONTINUATION	$613,384
2019	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	001	14	11/19/2018	COMPETING CONTINUATION	$118,109
2019	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	13	11/19/2018	NON-COMPETING CONTINUATION	-$118,109
														Subtotal = $613,384

Issue Date FY: 2018 ( Subtotal = $623,384 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	001	14	6/29/2018	COMPETING CONTINUATION	$623,384
2018	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	13	6/26/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $623,384

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	13	6/19/2017	NON-COMPETING CONTINUATION	$396,250
														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	Blood Diseases and Resources Research	000	12	6/30/2016	NON-COMPETING CONTINUATION	$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	Blood Diseases and Resources Research	000	11	7/1/2015	NON-COMPETING CONTINUATION	$390,306
														Subtotal = $390,306

Issue Date FY: 2014 ( Subtotal = $396,250 )
2014	2014	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	10	8/27/2014	COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2012 ( Subtotal = $388,575 )
2012	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	001	9	4/21/2012	NON-COMPETING CONTINUATION	$38,857
2012	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	9	12/24/2011	NON-COMPETING CONTINUATION	$349,718
														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	Blood Diseases and Resources Research	000	8	12/15/2010	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	Blood Diseases and Resources Research	000	7	12/16/2009	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	Blood Diseases and Resources Research	001	6	1/7/2009	COMPETING CONTINUATION	$392,500
2009	2007	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	5	1/7/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2007 ( Subtotal = $326,412 )
2007	2007	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	5	6/28/2007	NON-COMPETING CONTINUATION	$326,412
														Subtotal = $326,412

Issue Date FY: 2006 ( Subtotal = $336,161 )
2006	2006	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	4	6/28/2006	NON-COMPETING CONTINUATION	$336,161
														Subtotal = $336,161

Issue Date FY: 2005 ( Subtotal = $344,250 )
2005	2005	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	3	6/23/2005	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2004 ( Subtotal = $344,250 )
2004	2004	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	2	7/22/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$344,250
														Subtotal = $344,250

Issue Date FY: 2003 ( Subtotal = $329,174 )
2003	2003	CLEVELAND CLINIC FOUNDATION	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	1	7/11/2003	NEW	$329,174
														Subtotal = $329,174

Grand Total All Awards = $7,178,473

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Novel role of integrins in paracrine regulation of vasculature

Award Number: R01HL071625

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/14/2003

PERIOD OF PERFORMANCE END DATE: 06/30/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer