R35HL172107
Project Grant
Overview
Grant Description
From genetic association to function: pleiotropic novel genes and variants linking lipid metabolism and cardiovascular diseases - project summary.
Human genetic investigations have nominated hundreds of novel genomic loci harboring genes that influence a range of cardiovascular (CV) diseases and their risk factors, including plasma lipids. However, only a fraction of these novel loci have been investigated to determine the causal genes and underlying molecular mechanisms leading to increased risk of—or protection from—CV disease.
While LDL reduction is effective in reducing risk of atherosclerotic cardiovascular disease, other common cardiovascular diseases such as peripheral arterial disease, abdominal aortic aneurysm, and aortic stenosis have no effective non-surgical medical therapies. Importantly, a growing body of human genetic data has identified that even beyond CAD, these additional CV diseases have significant genetic associations with genomic loci/genes/variants that are also associated with plasma lipid traits.
This research program is focused on a systematic approach to fill some of the major gaps in knowledge that link these human genomic loci to new biology, disease pathogenesis and potential therapeutic targets. The goal is to provide a roadmap for how the hundreds of novel loci/genes/variants associated with CVD might ultimately be investigated in an efficient manner.
The focus will be on genes associated with both plasma lipid traits and at least one major cardiovascular disease. Due to the liver’s primary role in lipid and lipoprotein metabolism, the investigators will target liver-expressed genes. Furthermore, they will leverage naturally-occurring protein-coding variation in genes that influence plasma lipids and CVD in order to gain greater insight into the structure-function relationships of these proteins and relationship to phenotypes.
This is an ambitious program of research with two major research foci:
Focus 1: Interrogation of novel putatively causal genes at loci associated with both lipid traits and CV disease. Through systematic data ingestion and analyses of large-scale GWAS and sequencing data, the study team will generate (and refine) a prioritized list of liver-expressed genes at loci significantly associated with plasma lipids and at least one CV disease. Cell-based and murine model systems will be used, accompanied by human studies, to validate causal genes and gain insight into the physiological and molecular mechanisms by which they exert their influence.
Focus 2: Leveraging protein-coding variants to provide insight into structure-function properties of proteins influencing lipid traits and CV disease. Through systematic analyses of large-scale public and private genomic data linked to phenotypes, the investigators will develop a prioritized list of novel protein-coding variants associated with lipids and CVD and perform comparative functional studies in model systems and in human carriers.
The outcome of these studies is expected to establish a firm biological basis for a substantial number of novel genes/proteins and protein-coding variants that influence plasma lipoprotein metabolism and CV disease. The intent is to establish a paradigm by which novel genes/variants associated with NHLBI-related phenotypes can be efficiently validated and rapidly provided to the broader scientific community for further investigation.
Human genetic investigations have nominated hundreds of novel genomic loci harboring genes that influence a range of cardiovascular (CV) diseases and their risk factors, including plasma lipids. However, only a fraction of these novel loci have been investigated to determine the causal genes and underlying molecular mechanisms leading to increased risk of—or protection from—CV disease.
While LDL reduction is effective in reducing risk of atherosclerotic cardiovascular disease, other common cardiovascular diseases such as peripheral arterial disease, abdominal aortic aneurysm, and aortic stenosis have no effective non-surgical medical therapies. Importantly, a growing body of human genetic data has identified that even beyond CAD, these additional CV diseases have significant genetic associations with genomic loci/genes/variants that are also associated with plasma lipid traits.
This research program is focused on a systematic approach to fill some of the major gaps in knowledge that link these human genomic loci to new biology, disease pathogenesis and potential therapeutic targets. The goal is to provide a roadmap for how the hundreds of novel loci/genes/variants associated with CVD might ultimately be investigated in an efficient manner.
The focus will be on genes associated with both plasma lipid traits and at least one major cardiovascular disease. Due to the liver’s primary role in lipid and lipoprotein metabolism, the investigators will target liver-expressed genes. Furthermore, they will leverage naturally-occurring protein-coding variation in genes that influence plasma lipids and CVD in order to gain greater insight into the structure-function relationships of these proteins and relationship to phenotypes.
This is an ambitious program of research with two major research foci:
Focus 1: Interrogation of novel putatively causal genes at loci associated with both lipid traits and CV disease. Through systematic data ingestion and analyses of large-scale GWAS and sequencing data, the study team will generate (and refine) a prioritized list of liver-expressed genes at loci significantly associated with plasma lipids and at least one CV disease. Cell-based and murine model systems will be used, accompanied by human studies, to validate causal genes and gain insight into the physiological and molecular mechanisms by which they exert their influence.
Focus 2: Leveraging protein-coding variants to provide insight into structure-function properties of proteins influencing lipid traits and CV disease. Through systematic analyses of large-scale public and private genomic data linked to phenotypes, the investigators will develop a prioritized list of novel protein-coding variants associated with lipids and CVD and perform comparative functional studies in model systems and in human carriers.
The outcome of these studies is expected to establish a firm biological basis for a substantial number of novel genes/proteins and protein-coding variants that influence plasma lipoprotein metabolism and CV disease. The intent is to establish a paradigm by which novel genes/variants associated with NHLBI-related phenotypes can be efficiently validated and rapidly provided to the broader scientific community for further investigation.
Funding Goals
THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. 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
Pennsylvania
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 195% from $1,123,889 to $3,312,905.
Trustees Of The University Of Pennsylvania was awarded
Genetic Linkages Between Lipid Metabolism and Cardiovascular Diseases
Project Grant R35HL172107
worth $3,312,905
from National Heart Lung and Blood Institute in April 2024 with work to be completed primarily in Pennsylvania United States.
The grant
has a duration of 7 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 4/22/26
Period of Performance
4/1/24
Start Date
3/31/31
End Date
Funding Split
$3.3M
Federal Obligation
$0.0
Non-Federal Obligation
$3.3M
Total Obligated
Activity Timeline
Transaction History
Modifications to R35HL172107
Additional Detail
Award ID FAIN
R35HL172107
SAI Number
R35HL172107-467136708
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private 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
GM1XX56LEP58
Awardee CAGE
7G665
Performance District
PA-90
Senators
Robert Casey
John Fetterman
John Fetterman
Modified: 4/22/26