P01HL160487
Project Grant
Overview
Grant Description
New Approaches to Reduce Residual Cardiovascular Risk - PPG
Title: New Approaches to Reduce Residual Cardiovascular Risk
Summary/Abstract
In the last 40 years, significant progress has been made in reducing cardiovascular events by lowering plasma LDL-cholesterol (LDL-C). While statins and PCSK9 inhibitors effectively decrease LDL-C levels, significant residual risk of coronary heart disease (CHD) remains even in maximally treated individuals with low plasma levels of LDL-C. Epidemiological and genetic studies suggest that a significant proportion of the residual risk is due to elevated plasma levels of triglyceride-rich apoB-containing lipoproteins (apoBCLs).
The three projects that comprise this Program Project Grant (PPG) will elucidate new molecular mechanisms that regulate the synthesis, secretion, and metabolism of apoBCLs. Our PPG is comprised of distinguished investigators with a longstanding history of collaboration, five of whom (Goldstein, Brown, Hobbs, Horton, and Cohen) have worked together for 25 years.
In Project 1 of this new PPG, Radhakrishnan, Brown, and Goldstein have used an original and innovative screening protocol to identify a cholesterol-mimetic small molecule that binds to SCAP with high specificity and blocks activation of SREBPs, the transcription factors that activate genes required for the synthesis of cholesterol, fatty acids (FAs), and triglycerides (TGs). This compound will be used to elucidate the molecular mechanism by which SCAP senses sterols, enabling the first description of SCAP's cholesterol binding site at atomic resolution. The current cholesterol mimetic compound and more potent derivatives in development will be used to assess the clinical implications of a SCAP inhibitor for reduction of plasma apoBCLs.
In Project 2, Horton, Kim, and Liang have identified a new lipogenic enzyme complex in the liver. They will characterize components of the FA synthesis complex and determine how this complex interacts with additional FA modifying proteins and acyl-transferases required to synthesize TGs and apoBCLs. Completion of the proposed studies will identify new opportunities for therapeutic interventions to reduce the synthesis of FAs, TGs, and VLDL.
In Project 3, Hobbs and Cohen used population-based resequencing to identify loss-of-function mutations in angiopoietin-like (ANGPTL) 3 and 8. They showed that mutations in either protein result in lower plasma LDL-cholesterol and TG levels. Their studies will elucidate the mechanisms underlying the apoBCL lowering effects of ANGPTL3 and ANGPTL8. In the process, they will define a new pathway that promotes clearance of apoBCLs independently of the LDL receptor.
The research projects will be supported by three cores: Administrative, Tissue Culture & Antibody Production, and Mass Spectrometry. Members of this PPG have a long record of collaborative interactions and exceptional productivity. We will continue to focus on bold hypotheses designed to answer critical questions. The investigators take special pride in publishing papers that are characterized by originality and scientific rigor. The successful completion of our projects holds great promise for exposing new therapeutic opportunities for the reduction of plasma apoBCLs and residual cardiovascular risk.
Title: New Approaches to Reduce Residual Cardiovascular Risk
Summary/Abstract
In the last 40 years, significant progress has been made in reducing cardiovascular events by lowering plasma LDL-cholesterol (LDL-C). While statins and PCSK9 inhibitors effectively decrease LDL-C levels, significant residual risk of coronary heart disease (CHD) remains even in maximally treated individuals with low plasma levels of LDL-C. Epidemiological and genetic studies suggest that a significant proportion of the residual risk is due to elevated plasma levels of triglyceride-rich apoB-containing lipoproteins (apoBCLs).
The three projects that comprise this Program Project Grant (PPG) will elucidate new molecular mechanisms that regulate the synthesis, secretion, and metabolism of apoBCLs. Our PPG is comprised of distinguished investigators with a longstanding history of collaboration, five of whom (Goldstein, Brown, Hobbs, Horton, and Cohen) have worked together for 25 years.
In Project 1 of this new PPG, Radhakrishnan, Brown, and Goldstein have used an original and innovative screening protocol to identify a cholesterol-mimetic small molecule that binds to SCAP with high specificity and blocks activation of SREBPs, the transcription factors that activate genes required for the synthesis of cholesterol, fatty acids (FAs), and triglycerides (TGs). This compound will be used to elucidate the molecular mechanism by which SCAP senses sterols, enabling the first description of SCAP's cholesterol binding site at atomic resolution. The current cholesterol mimetic compound and more potent derivatives in development will be used to assess the clinical implications of a SCAP inhibitor for reduction of plasma apoBCLs.
In Project 2, Horton, Kim, and Liang have identified a new lipogenic enzyme complex in the liver. They will characterize components of the FA synthesis complex and determine how this complex interacts with additional FA modifying proteins and acyl-transferases required to synthesize TGs and apoBCLs. Completion of the proposed studies will identify new opportunities for therapeutic interventions to reduce the synthesis of FAs, TGs, and VLDL.
In Project 3, Hobbs and Cohen used population-based resequencing to identify loss-of-function mutations in angiopoietin-like (ANGPTL) 3 and 8. They showed that mutations in either protein result in lower plasma LDL-cholesterol and TG levels. Their studies will elucidate the mechanisms underlying the apoBCL lowering effects of ANGPTL3 and ANGPTL8. In the process, they will define a new pathway that promotes clearance of apoBCLs independently of the LDL receptor.
The research projects will be supported by three cores: Administrative, Tissue Culture & Antibody Production, and Mass Spectrometry. Members of this PPG have a long record of collaborative interactions and exceptional productivity. We will continue to focus on bold hypotheses designed to answer critical questions. The investigators take special pride in publishing papers that are characterized by originality and scientific rigor. The successful completion of our projects holds great promise for exposing new therapeutic opportunities for the reduction of plasma apoBCLs and residual cardiovascular risk.
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
Texas
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 298% from $2,484,600 to $9,888,708.
The University Of Texas Southwestern Medical Center was awarded
Reducing Residual Cardiovascular Risk: New Approaches & Molecular Mechanisms
Project Grant P01HL160487
worth $9,888,708
from National Heart Lung and Blood Institute in January 2021 with work to be completed primarily in Texas United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity NHLBI Program Project Applications (P01 Clinical Trials Optional).
Status
(Ongoing)
Last Modified 9/24/25
Period of Performance
1/1/22
Start Date
12/31/26
End Date
Funding Split
$9.9M
Federal Obligation
$0.0
Non-Federal Obligation
$9.9M
Total Obligated
Activity Timeline
Transaction History
Modifications to P01HL160487
Additional Detail
Award ID FAIN
P01HL160487
SAI Number
P01HL160487-2446950557
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled 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
YZJ6DKPM4W63
Awardee CAGE
1CNP4
Performance District
TX-90
Senators
John Cornyn
Ted Cruz
Ted Cruz
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) | $4,969,200 | 100% |
Modified: 9/24/25