P01HL172729

Disease mechanisms of early pulmonary fibrosis - Program project summary to develop novel, transformative therapies that substantially reduce the burden of morbidity and mortality from progressive pulmonary fibrosis (PF), a fundamentally new conceptualization of PF is required.

It is becoming clear that lung fibrosis is a consequence, rather than the primary driver, of disease pathobiology and represents the culmination of a lengthy period of pre-clinical disease progression driven by repetitive cycles of epithelial injury and dysfunctional repair.

Rather than focusing on slowing progression of established PF, we propose that therapeutic efforts should be directed at preventing the development of symptomatic PF.

This program will focus primarily on the pre-symptomatic period, which represents the ideal time for interventions to modify the course of PF.

Our overall objective is to re-shape understanding of the natural history of PF by investigating the transcriptomic, genetic, epigenetic, metabolic, and exposome-related signatures that contribute to disease initiation and early progression.

Our long-term goals are to use the knowledge gained in this program to develop new strategies for pre-clinical risk stratification and to identify novel approaches for disease prevention and treatment.

This program consists of 4 projects and 3 cores and will leverage our ongoing cohort study of asymptomatic relatives of patients with familial PF (FPF).

Project 1 titled “Mechanisms of early disease progression in FPF” will investigate single-cell transcriptomics from blood and bronchoalveolar lavage cells to identify critical mechanisms driving pre-clinical FPF and develop better biomarkers for identification of early disease.

Project 2 titled “Environmental exposures in pre-clinical FPF” will use cutting-edge technology combined with standardized assessments to measure real-time exposures and identify specific environmental toxins that contribute to the early development of PF.

Project 3 titled “Functional genomic mechanisms of epithelial dysfunction in pulmonary fibrosis” will utilize single-cell multiomics from lung biopsies and patient-derived organoid models to investigate the mechanisms through which genetic factors interact with environmentally-driven stimuli to drive the initiation and progression of PF.

Project 4 titled “Defining the molecular natural history of early and progressive pulmonary fibrosis” will utilize state-of-the-art spatial transcriptomic technologies and ex vivo culture models to generate a spatially-resolved molecular atlas of pre-clinical and progressive PF.

The administrative core houses expertise to manage and support the entire program, the clinical and biospecimen core will conduct all studies involving human subjects, and the genomics core will support data acquisition, analysis, storage, and dissemination.

Together, we anticipate that the highly-integrated and synergistic nature of this proposal will result in a revolution in understanding of early PF pathogenesis and facilitate future studies aimed at disease prevention.

Regents Of The University Of Michigan

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.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

NHLBI Program Project Applications (P01 Clinical Trials Optional) (PAR-21-088)

Amendment Since initial award the total obligations have increased 99% from $2,857,933 to $5,687,616.