R01HL162367
Project Grant
Overview
Grant Description
The role of adaptor protein Disabled-2 in maintaining endothelial cell function in atherosclerosis - Project Summary/Abstract
Cardiovascular diseases are often associated with impaired responses from the endothelium, which results from endothelial cell dysfunction. Endothelial cell dysfunction causes endothelial activation and sub-endothelial retention of modified low-density lipoprotein (LDL) particles, leading to the recruitment of immune and inflammatory cells to the intima, which initiate atheromatous plaque build-up. Of major importance, transitioning from a stable to vulnerable atheroma fuels myocardial infarction and stroke, posing enormous health challenges with the highest morbidity and mortality in the United States.
New research is urgently needed to uncover critical pathophysiological mechanisms and identify molecules that limit endothelial dysfunction. This has led us to determine a novel and indispensable role for an endocytic adaptor protein called Disabled Homolog 2 (Dab2), which participates in clathrin-mediated endocytosis in addition to moonlighting as a tumor suppressor. Curiously, little to no prior work has been done to identify its role in endothelial cells.
Our pilot assessment has revealed that Dab2 levels are strikingly decreased in the atherosclerotic endothelium of mouse and human fatty streaks—suggesting a protective role in atherogenesis. As the atheroprotective effects of Dab2 are poorly understood in the context of endothelial cells, we created endothelial-specific inducible Dab2 knockout mice (EC-IDAB2KO) and bred them to an ApoE-null background (EC-DAB2IKO/ApoE-/-). Western diet-fed EC-IDAB2KO/ApoE-/- mice exhibit heightened arterial inflammation and more severe plaque formation; yet, the molecular mechanisms and signaling pathways that direct Dab2 to combat arterial inflammation are completely unknown.
Our initial investigation indicates that Dab2 expression is upregulated in response to atheroprotective flow, and Dab2 deficiency in human aortic endothelial cells suppresses endothelial nitric oxide synthase (eNOS) activation. To ensure the clinical relevance of our work, we are employing an innovative nanotechnology to deliver Dab2 mRNA to the atherogenic endothelium using an engineered nanoparticle to restore Dab2 function. This technology increases Dab2 expression in the atheroma, which restrains plaque progression in ApoE-/- mice.
The goal of this proposal is to define the signaling mechanisms underpinning the essential role of Dab2 in protecting the atherogenic endothelium. To this end, we seek to determine molecular mechanisms by which Dab2 curbs arterial inflammation and activates eNOS in endothelial cells. Our possession of innovative targeting reagents and novel animal models will greatly facilitate our paradigm-shifting endeavor.
If fruitful, the exciting work proposed in our application will provide a foundation for the development of new treatments to benefit patients at risk for heart attacks and strokes.
Cardiovascular diseases are often associated with impaired responses from the endothelium, which results from endothelial cell dysfunction. Endothelial cell dysfunction causes endothelial activation and sub-endothelial retention of modified low-density lipoprotein (LDL) particles, leading to the recruitment of immune and inflammatory cells to the intima, which initiate atheromatous plaque build-up. Of major importance, transitioning from a stable to vulnerable atheroma fuels myocardial infarction and stroke, posing enormous health challenges with the highest morbidity and mortality in the United States.
New research is urgently needed to uncover critical pathophysiological mechanisms and identify molecules that limit endothelial dysfunction. This has led us to determine a novel and indispensable role for an endocytic adaptor protein called Disabled Homolog 2 (Dab2), which participates in clathrin-mediated endocytosis in addition to moonlighting as a tumor suppressor. Curiously, little to no prior work has been done to identify its role in endothelial cells.
Our pilot assessment has revealed that Dab2 levels are strikingly decreased in the atherosclerotic endothelium of mouse and human fatty streaks—suggesting a protective role in atherogenesis. As the atheroprotective effects of Dab2 are poorly understood in the context of endothelial cells, we created endothelial-specific inducible Dab2 knockout mice (EC-IDAB2KO) and bred them to an ApoE-null background (EC-DAB2IKO/ApoE-/-). Western diet-fed EC-IDAB2KO/ApoE-/- mice exhibit heightened arterial inflammation and more severe plaque formation; yet, the molecular mechanisms and signaling pathways that direct Dab2 to combat arterial inflammation are completely unknown.
Our initial investigation indicates that Dab2 expression is upregulated in response to atheroprotective flow, and Dab2 deficiency in human aortic endothelial cells suppresses endothelial nitric oxide synthase (eNOS) activation. To ensure the clinical relevance of our work, we are employing an innovative nanotechnology to deliver Dab2 mRNA to the atherogenic endothelium using an engineered nanoparticle to restore Dab2 function. This technology increases Dab2 expression in the atheroma, which restrains plaque progression in ApoE-/- mice.
The goal of this proposal is to define the signaling mechanisms underpinning the essential role of Dab2 in protecting the atherogenic endothelium. To this end, we seek to determine molecular mechanisms by which Dab2 curbs arterial inflammation and activates eNOS in endothelial cells. Our possession of innovative targeting reagents and novel animal models will greatly facilitate our paradigm-shifting endeavor.
If fruitful, the exciting work proposed in our application will provide a foundation for the development of new treatments to benefit patients at risk for heart attacks and strokes.
Awardee
Funding Goals
TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Massachusetts
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 274% from $812,576 to $3,039,522.
Children's Hospital Corporation was awarded
Role of Dab2 in Atherosclerotic Endothelial Protection
Project Grant R01HL162367
worth $3,039,522
from National Heart Lung and Blood Institute in December 2021 with work to be completed primarily in Massachusetts United States.
The grant
has a duration of 4 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 9/5/25
Period of Performance
12/1/21
Start Date
11/30/25
End Date
Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for R01HL162367
Transaction History
Modifications to R01HL162367
Additional Detail
Award ID FAIN
R01HL162367
SAI Number
R01HL162367-1177143716
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Funding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Awardee UEI
Z1L9F1MM1RY3
Awardee CAGE
2H173
Performance District
MA-90
Senators
Edward Markey
Elizabeth Warren
Elizabeth Warren
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Heart, Lung, and Blood Institute, National Institutes of Health, Health and Human Services (075-0872) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,582,002 | 100% |
Modified: 9/5/25