Autophagy is disrupted in many disease conditions and the underlying mechanism is still unclear. Diseases such as Huntington's, Alzheimer's, cystic fibrosis (CF) and Parkinson's diseases are characterized by aggregates of mutant proteins and are often associated with weak autophagy activity. In this proposal, we focus on CF which is the most common inherited lethal disease among Caucasians, and is caused by mutations in the cftr gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Our recent studies demonstrated that macrophages from CF patients and CF mice have weak autophagy. Furthermore, we have identified specific microRNAs targeting essential autophagy molecules that are elevated in macrophages from CF patients and CF mice associated with low expression of the predicted autophagy gene targets. We therefore hypothesize that altered autophagy in macrophages of CF patients is due to the high levels of certain miRs. Weak autophagy then contributes to the chronic infection and excessive inflammation observed in the lung of CF patients, and loss of pulmonary function. Notably, our data also suggest that weak autophagy contributes to low CFTR function. This grant proposal will (a) determine the epigenetic changes and other mechanisms leading to increased expression of these specific miRNAs in CF patients and CF mice, and (b) establish that reducing the expression of these specific miRNAs will correct CFTR function, restore bacterial clearance, and alleviate excessive inflammation.

Public Health Relevance

Cystic fibrosis (CF) is the most common inherited lethal disease affecting Caucasian people and many of them suffer and die from severe inflammation that accompanies bacterial infections in the lung. We found that CF patients have a weak innate immune response called autophagy whereas in healthy cells, autophagy controls infection and inflammation. To understand why CF patients have weak autophagy we will examine small molecules (MicroRNA) that play a role in how much a certain protein is made to identify new drug targets for CF patients to save their lives.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127651-04
Application #
9520396
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Sheridan, John T
Project Start
2015-07-20
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Abu Khweek, Arwa; Amer, Amal O (2018) Factors Mediating Environmental Biofilm Formation by Legionella pneumophila. Front Cell Infect Microbiol 8:38
Krause, Kathrin; Kopp, Benjamin T; Tazi, Mia F et al. (2018) The expression of Mirc1/Mir17-92 cluster in sputum samples correlates with pulmonary exacerbations in cystic fibrosis patients. J Cyst Fibros 17:454-461
Abdelaziz, Dalia H A; Khalil, Hany; Cormet-Boyaka, Estelle et al. (2015) The cooperation between the autophagy machinery and the inflammasome to implement an appropriate innate immune response: do they regulate each other? Immunol Rev 265:194-204