R01HL163984

Noradrenergic Mechanisms of IPF - Abstract

The pulmonary fibrosis that accompanies many conditions is characterized by progressive scar formation in the adult human lung. Regardless of the underlying disease state, the presence of this complication portends a worse outcome that is curable only by lung transplantation.

Proposed pathogenic mechanisms suggest a poorly understood interaction between epithelial cells and fibroblasts that is orchestrated by microenvironmental cues. Understanding these aspects in the fibrotic microenvironment is of particular importance in diseases such as idiopathic pulmonary fibrosis (IPF) where patients present with established and often progressive disease. As a result, identification of intervenable processes that can be targeted for safe and effective therapies remains a critical unmet need.

It is therefore relevant that in a groundbreaking set of studies, we have found that fibrotic lungs are enriched for ectopically patterned adrenergic nerves, that these nerves drive fibrosis by releasing NA, and that NA-driven fibrosis can be treated with A1 adrenoreceptor antagonists. This axis is active in IPF where lung tissues are enriched for markers of adrenergic innervation and NA, and patients treated with A1 adrenoreceptor antagonists experience improved clinical outcomes.

We will now determine how NA accumulates in fibrotic lungs and define its fibrogenic functions. For example, while we have found that adrenergic nerve remodeling is stimulated by the dependence receptor deleted in colorectal carcinoma (DCC), the mechanism(s) of this observation are unknown. We have found that fibrotic lung macrophages are deficient in NA catabolism machinery, but whether they contribute to fibrosis via perturbed NA recycling has not been shown. Finally, we have found an association between fibroblast proliferation and A1 adrenoreceptor subtype ADRA1D in fibrotic mouse models and in human IPF that requires more study.

This application will explore the mechanistic impact and therapeutic potential of these findings using a unified vision and conceptual framework that will study how nerve-derived NA accumulates in the lung and causes fibrosis. We propose an integrated project that pursues three independent aims using a translational platform combining two animal models, manipulation of adrenergic nerves, neuroengineering, cell-specific knockout mice, genetic and pharmacologic gain and loss of function approaches, ex vivo study of human cells and tissues, single-cell sequencing, and microCT.

The first aim will probe whether adrenergic nerve remodeling and accumulation of fibrostimulatory NA requires expression of the dependence receptor deleted in colorectal carcinoma (DCC) on adrenergic nerves in the lung. The second aim will determine if perturbed NA recycling by macrophages exacerbates fibrosis in animal models and in human cells and tissues. The third aim will use cell-specific knockout mice and primary human cells and tissues to determine whether NA-associated lung fibrosis requires ADRA1D-expressing fibroblasts.

If successful, our project will produce paradigm-shifting results that will change the way we view – and treat – fibrosis in the adult lung.

Yale Univ

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.837 - Cardiovascular Diseases Research

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

New Haven, Connecticut 065191612 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)

Amendment Since initial award the End Date has been extended from 02/28/26 to 03/31/30 and the total obligations have increased 407% from $723,943 to $3,667,306.