R01AI171390

Respiratory sphingolipid synthesis involved in airway hyperreactivity and viral-triggered asthma - Project Summary

Asthma results from a complex interplay between genetic background and environmental triggers. The 17q21 asthma susceptibility locus is strongly linked to childhood asthma through ORMDL3. ORMDL3 regulates serine-palmitoyl CoA transferase (SPT), the critical enzyme for the de novo synthesis of sphingolipids. We demonstrated that decreased SPT activity leads to airway hyperreactivity.

There has since been increasing evidence that sphingolipid metabolism is altered in airway epithelial cells and animal models of ORMDL3-associated asthma. We have recently shown that children with asthma have decreased sphingolipid synthesis, especially in the presence of asthma risk 17q21 genotypes. 17q21 genotypes are also linked to the risk of developing asthma following respiratory infections with human rhinovirus (HRV). This is relevant as HRV is also the most common trigger for asthma attacks.

Supported by preliminary data in mice and airway epithelial cells demonstrating strong similarities in sphingolipid levels and gene expression between HRV infection and sphingolipid deficiency, we hypothesize that HRV infection can further impair sphingolipid synthesis. We propose to study the effects of HRV on sphingolipid synthesis in children with asthma and airway epithelial cells.

These studies could then further solidify the central role of sphingolipids in asthma pathogenesis that has been predicted by the commonality and the strong association of 17q21 genotypes to asthma. Two specific aims are proposed to assess the overall hypothesis that the sphingolipid de novo synthesis pathway is critical not only for asthma pathogenesis but also in response to the most common trigger for asthma attacks.

In Aim 1, we will determine sphingolipid synthesis in the respiratory tract in children with asthma and HRV infection. Sphingolipids will be assessed in nasal fluid, blood, and gene expression in nasal cells obtained from children during and after the resolution of HRV-triggered asthma attacks. In a subaim, we will evaluate the effects of HRV on sphingolipid metabolism and gene expression in primary human airway epithelial cells (HAEC) with homozygous for a common 17q21 asthma variation that leads to decreased blood sphingolipids in children with asthma. HAEC from an established biorepository from adult donors and nasal brushings from children all grown at air-liquid interface will be infected with HRV and RSV and evaluated for effects on sphingolipid synthesis.

For Aim 2, we will test the hypothesis that the altered ratio of the sphingolipid mediator sphingosine 1-phosphate and sphinganine 1 phosphate, which we found in SPT deficiency and children with the 17q21 asthma risk genotypes, leads to airway hyperreactivity.

Overall, these studies not only inform on the role of sphingolipids in the pathogenesis of asthma and the relation to its most common trigger but may lead to new therapeutic approaches involving sphingolipid metabolism.

Weill Medical College Of Cornell University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS; TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 01/31/28 to 01/31/29 and the total obligations have increased 277% from $884,376 to $3,333,007.