P01HL158507

Scientific Innovation for Personalized Severe Asthma Management - Project Summary/Abstract

Our overall goal is to characterize the cell biology and physiology of recently identified mechanisms underlying severe asthma. Severe asthma is a disabling obstructive lung disease that accounts for the majority of the morbidity and mortality associated with asthma. It also incurs annual healthcare costs in excess of $10 billion in the United States alone. Severe asthma has been a particular focus of our therapeutic development efforts.

We have discovered and studied three novel mechanisms relevant to severe asthma. These include the role in severe asthma of: 1) SS2 adrenergic receptor regulation by S-nitrosylation; 2) airway acidification; and 3) androgen signaling. Each of these three mechanisms has the potential to be treated with novel, personalized therapies that will be studied in a complementary fashion in the third aim of each project.

Three synergistic proposed projects are proposed: Project 1, S-nitrosylation signaling in severe asthma; Project 2, airway pH regulation in severe asthma; and Project 3, androgen signaling in severe asthma. Note that a substantial amount of the science, and most of the proposed cores, are currently incorporated in an NHLBI-sponsored translational P01 at our two institutions, Indiana University and Case Western Reserve University. However, the NHLBI is not planning to renew its translational P01 initiative.

What this means for the current proposal, however, is that the scientific interface, as well as the cores, are currently operational; and they are not duplicated at either institution. We propose to continue these core functions in the current proposal.

The three projects have scientific synergy. For example, detrimental denitrosylation (Project 1) is reversed both by airway alkalization (Project 2) and by airway epithelial androgen treatment (Project 3). Interleukin 17, which decreases airway epithelial S-nitrosothiol signaling (Project 1), is inhibited by airway alkalization (Project 2) and androgen receptor signaling (Project 3). Interleukin 4 gene expression appears to be inhibited both by human airway alkalization (Project 2) and by androgen receptor signaling (Project 3). These and related interactions will be studied in detail.

The program also has robust operational synergy. Each project will make use of each core. In particular, each will use data and specimens from the Research Bronchoscopy and Biospecimens Core and from the Severe Asthma Clinical Trials Core. Each will use cells from the Primary Human Airway Cell Culture Core. Each will rely heavily on the Pulmonary Biostatistics Core for data analysis. All projects and cores will be coordinated by an Administrative Core. Note that the Administrative Core will also assist all projects with data dissemination, with speakers, and with advisory boards.

None of the three projects would be able to support these core functionalities as an independent R01. At the conclusion of this program, we anticipate having used our basic science innovations to develop at least three novel approaches to managing severe asthma.

Trustees Of Indiana University

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]

Indianapolis, Indiana 462025254 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 396% from $2,420,712 to $12,001,334.