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P01HL169188

Project Grant

Overview

Grant Description
Integrated mechanisms of primary and chronic graft dysfunction following lung transplantation - Lung transplantation is increasingly used to treat an expanding list of end-stage lung diseases, resulting in an over >50% increase in the number of lung transplant procedures in the US in the last decade.

Unfortunately, survival following lung transplant is the worst amongst solid organs with only 80% and 50% of patients alive at 1 and 5 years, respectively.

Primary graft dysfunction (PGD) affects over 50% of recipients within 24 hours of transplantation and has emerged as the most important risk factor for both short-term mortality and long-term graft loss from chronic lung allograft dysfunction (CLAD).

The investigators in this PPG have made important contributions to a growing molecular understanding of the complex interplay between immune and lung parenchymal cells that underlie PGD and CLAD.

In Project 1, we dissect molecular mechanisms underlying our discovery that lung restricted alloantibodies (LRA), present in over 30% of lung transplant recipients, are associated with PGD.

In Project 2, we dissect physiologic and molecular mechanisms underlying prevalent abnormalities in esophageal function that lead to acid aspiration and worsen CLAD severity.

In Project 3, we will credential profibrotic MOAMs as causal drivers of lung fibrosis in murine models and in patients with CLAD.

In Project 4, ESI, we test whether mitochondrial dysfunction in the alveolar epithelium predisposes lung transplant recipients to pathologic activation of the integrated stress response (ISR) that precludes lung repair.

Together our published and preliminary data support our overarching hypothesis that acute neutrophil-mediated lung injury mechanisms such as PGD and acid aspiration drive CLAD progression by promoting the development of LRA, recruiting profibrotic MOAM, and inducing epithelial cell mitochondrial damage causing an ISR-mediated barrier to epithelial repair.

We will test this hypothesis in 4 interrelated and synergistic projects.

Project 1. To determine whether LRA interact with donor derived NCM and recipient CM to worsen PGD via the activation of complement dependent and independent pathways.

Project 2. To determine whether physiologic abnormalities in the esophagus after lung transplant cause gastric aspiration that induces LRA and CLAD progression via neutrophils and MOAM.

Project 3. To determine whether CSF1 drives the recruitment and retention of profibrotic MOAM and whether their detection in bronchoalveolar lavage fluid can serve as a biomarker for CLAD.

Project 4. To determine whether mitochondrial dysfunction in the airway and alveolar epithelium results in pathologic activation of the ISR that precludes normal epithelial repair to promote CLAD.

The Human and Clinical Phenotyping Core (Core B), Mouse and Cell Phenotyping Core (Core C) and Administrative Core (Core A) will support these synergistic projects using murine models and clinical and molecular data collected from lung transplant recipients to identify actionable pathways that can be therapeutically targeted to improve lung transplant outcomes.
Funding Goals
THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. 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.
Place of Performance
Chicago, Illinois 606113015 United States
Geographic Scope
Single Zip Code
Analysis Notes
Amendment Since initial award the total obligations have increased 100% from $2,803,961 to $5,608,027.
Northwestern University was awarded Enhancing Lung Transplant Outcomes: Mechanisms of Graft Dysfunction Project Grant P01HL169188 worth $5,608,027 from National Heart Lung and Blood Institute in September 2024 with work to be completed primarily in Chicago Illinois United States. The grant has a duration of 4 years 10 months 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 8/20/25

Period of Performance
9/17/24
Start Date
7/31/29
End Date
19.0% Complete

Funding Split
$5.6M
Federal Obligation
$0.0
Non-Federal Obligation
$5.6M
Total Obligated
100.0% Federal Funding
0.0% Non-Federal Funding

Activity Timeline

Interactive chart of timeline of amendments to P01HL169188

Transaction History

Modifications to P01HL169188

Additional Detail

Award ID FAIN
P01HL169188
SAI Number
P01HL169188-552289722
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
KG76WYENL5K1
Awardee CAGE
01725
Performance District
IL-05
Senators
Richard Durbin
Tammy Duckworth
Modified: 8/20/25