R01HL161858
Project Grant
Overview
Grant Description
Early Myocardial Remodeling and Progressive Kidney Function Decline in Type 1 Diabetes - Summary
A large proportion of the excess cardiovascular disease (CVD) morbidity and mortality experienced by individuals with Type 1 Diabetes (T1D) occur in conjunction with Diabetic Kidney Disease (DKD). DKD is associated with a striking increase in the risk of Coronary Artery Disease (CAD) and heart failure. The latter is frequently due to the development of Diabetic Cardiomyopathy, which is a diabetes-specific alteration of the myocardium.
The etiologic links between DKD and cardiomyopathy are not clear, but preliminary data from our group suggest a pivotal role of the kidney function decline component of DKD rather than albuminuria. Specifically, using an MRI-derived marker of cardiomyocyte size, we have observed that patients with T1D who are losing kidney function but still have preserved Glomerular Filtration Rate (GFR) have subclinical signs of myocardial remodeling. This is indicated by a larger cardiomyocyte size and a reduction of myocardial fiber shortening during systole compared to T1D patients with stable kidney function.
The overall goal of this collaborative proposal, in response to RFA-HL-21-014, is to take advantage of the latest developments in cardiac imaging and biomarker platforms to characterize the cardiac involvement in patients with T1D and DKD. The focus will be on the initial events in the development of Diabetic Cardiomyopathy.
The study will involve "GFR decliners" (patients with T1D and CKD stage 1-3A who have experienced GFR loss of at least 3 mL/min/year in the previous 3-6 years, n=100), "GFR non-decliners" (n=100) with T1D and CKD stage 1-3A, and non-diabetic controls (n=100) of similar age and CKD stage. These participants will undergo a gadolinium-enhanced cardiac magnetic resonance (CMR) and a gated cardiac CT scan to quantify coronary artery calcium (CAC).
The study aims to address the following specific aims:
1. Evaluate the presence and severity of myocardial remodeling among T1D patients and assess its relationship with early progressive kidney function decline. Cardiomyocyte size (TIC) and interstitial fibrosis (measured as extracellular volume [ECV]) will be quantified by CMR and compared among GFR decliners, GFR non-decliners, and non-diabetic subjects. These measurements will also be related to albuminuria and the presence and severity of CAD.
2. Assess the relative contribution of cardiomyocyte hypertrophy and interstitial fibrosis to impaired cardiac function among T1D patients. Indices of cardiac function and myocardial strain will be derived from the CMR data and evaluated for their association with cardiomyocyte size (TIC) and interstitial fibrosis (ECV), in relation to the severity of concomitant CAD.
3. Gain insights into the disease processes involved in the etiology of myocardial remodeling and assess whether these overlap with those involved in the progressive kidney function decline. Targeted studies will focus on serum proteins implicated in heart failure or previously associated with an increased risk of GFR loss. Untargeted studies will leverage the latest developments in multiplexed assays to evaluate serum protein profiles in a systematic fashion.
With the information generated by this study, we will be optimally positioned to develop new strategies and possibly new drugs to prevent CVD in T1D.
A large proportion of the excess cardiovascular disease (CVD) morbidity and mortality experienced by individuals with Type 1 Diabetes (T1D) occur in conjunction with Diabetic Kidney Disease (DKD). DKD is associated with a striking increase in the risk of Coronary Artery Disease (CAD) and heart failure. The latter is frequently due to the development of Diabetic Cardiomyopathy, which is a diabetes-specific alteration of the myocardium.
The etiologic links between DKD and cardiomyopathy are not clear, but preliminary data from our group suggest a pivotal role of the kidney function decline component of DKD rather than albuminuria. Specifically, using an MRI-derived marker of cardiomyocyte size, we have observed that patients with T1D who are losing kidney function but still have preserved Glomerular Filtration Rate (GFR) have subclinical signs of myocardial remodeling. This is indicated by a larger cardiomyocyte size and a reduction of myocardial fiber shortening during systole compared to T1D patients with stable kidney function.
The overall goal of this collaborative proposal, in response to RFA-HL-21-014, is to take advantage of the latest developments in cardiac imaging and biomarker platforms to characterize the cardiac involvement in patients with T1D and DKD. The focus will be on the initial events in the development of Diabetic Cardiomyopathy.
The study will involve "GFR decliners" (patients with T1D and CKD stage 1-3A who have experienced GFR loss of at least 3 mL/min/year in the previous 3-6 years, n=100), "GFR non-decliners" (n=100) with T1D and CKD stage 1-3A, and non-diabetic controls (n=100) of similar age and CKD stage. These participants will undergo a gadolinium-enhanced cardiac magnetic resonance (CMR) and a gated cardiac CT scan to quantify coronary artery calcium (CAC).
The study aims to address the following specific aims:
1. Evaluate the presence and severity of myocardial remodeling among T1D patients and assess its relationship with early progressive kidney function decline. Cardiomyocyte size (TIC) and interstitial fibrosis (measured as extracellular volume [ECV]) will be quantified by CMR and compared among GFR decliners, GFR non-decliners, and non-diabetic subjects. These measurements will also be related to albuminuria and the presence and severity of CAD.
2. Assess the relative contribution of cardiomyocyte hypertrophy and interstitial fibrosis to impaired cardiac function among T1D patients. Indices of cardiac function and myocardial strain will be derived from the CMR data and evaluated for their association with cardiomyocyte size (TIC) and interstitial fibrosis (ECV), in relation to the severity of concomitant CAD.
3. Gain insights into the disease processes involved in the etiology of myocardial remodeling and assess whether these overlap with those involved in the progressive kidney function decline. Targeted studies will focus on serum proteins implicated in heart failure or previously associated with an increased risk of GFR loss. Untargeted studies will leverage the latest developments in multiplexed assays to evaluate serum protein profiles in a systematic fashion.
With the information generated by this study, we will be optimally positioned to develop new strategies and possibly new drugs to prevent CVD in T1D.
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 Agency
Place of Performance
Boston,
Massachusetts
022155306
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 289% from $821,720 to $3,199,007.
Joslin Diabetes Center was awarded
T1D & DKD: Myocardial Remodeling in Kidney Decline
Project Grant R01HL161858
worth $3,199,007
from the National Institute of Diabetes and Digestive and Kidney Diseases in December 2021 with work to be completed primarily in Boston Massachusetts United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research.
The Project Grant was awarded through grant opportunity Understanding and Reducing Cardiovascular Disease in Type 1 Diabetes Mellitus (R01 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 11/20/24
Period of Performance
12/24/21
Start Date
11/30/26
End Date
Funding Split
$3.2M
Federal Obligation
$0.0
Non-Federal Obligation
$3.2M
Total Obligated
Activity Timeline
Transaction History
Modifications to R01HL161858
Additional Detail
Award ID FAIN
R01HL161858
SAI Number
R01HL161858-2273859587
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
75NK00 NIH NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Awardee UEI
UUUMQVGJNNX1
Awardee CAGE
1Y457
Performance District
MA-07
Senators
Edward Markey
Elizabeth Warren
Elizabeth Warren
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Health and Human Services (075-0884) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,530,572 | 100% |
Modified: 11/20/24