The goal of this proposal is to address the urgent need for asthma patients by taking advantage of the recent breakthroughs in the field of Ca2+ signaling to benefit asthma therapy. Multiple lines of evidence suggest an important role for CRAC (Ca2+-release-activated Ca2+) channels in asthma. Ca2+ entry via CRAC channels is a predominant mechanism of intracellular Ca2+ elevation in T cells and mast cells that are important players in airway allergic inflammation. Recently, we and others identified Orai1 (CRACM1, TMEM142) as a long-sought pore component of CRAC channels. Discovery of CRAC channel components provides a new opportunity to develop asthma therapy by targeting CRAC channels to suppress the functions of TH2 cells. In this proposal, we will test this possibility using two novel and strong experimental tools- Orai1 conditional knockout mice with T cell- specific deletion of Orai1, and small molecule blockers of Orai1 that we have recently identified from high throughput chemical library screenings. Our studies will first examine the function of Orai1 in differentiation of TH2 cells and in asthma using conditionally targeted Orai1 knockout mice (Aim 1). We will check how the deficiency of Orai1 will influence the transcriptional programs for TH2 differentiation. We will also determine the role of Orai1 using an animal model of asthma by measuring lung functions (e.g. lung resistance and dynamic compliance). We then correlate the obtained basic knowledge with identification of novel therapeutic methods to treat asthma using small molecule blockers of Orai1 (Aim 2). Using specific blockers, we also plan to determine the role of Orai1 in the functions of B cells and mast cells. The proposed studies are conceptually and technically novel and innovative because we will be the first to test the therapeutic potential of blocking Orai1 in the disease settings of asthma using unique tools we have established. Thus, our studies will have a broad impact on basic understanding of the function of Ca2+ signaling in allergic T cells, its role in other allergc cell functions (e.g. B cells, mast cells, type 2 innate immune cells), and development of novel therapy to treat severe forms of allergic and atopic inflammatory diseases.

Public Health Relevance

The long-term goal of this proposal is to address the urgent need for asthma patients by taking advantage of the recent discovery of the pore component of CRAC channels, Orai1 that plays a crucial for activation of type-2 helper T cells and mast cells. Our studies will first examine the function of Orai1 in asthma, and then correlate the obtained basic knowledge with identification of novel therapeutic methods to treat asthma using small molecule blockers of Orai1 that we have recently identified form the newly designed high throughput screens. Thus, the proposed studies are novel and innovative, and they will have a broad impact on basic understanding of the function of Ca2+ signaling in allergic T cells, its role in other allergic cell functions, and development of novel therapy to treat allergic and atopic inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI109059-01A1
Application #
9042630
Study Section
Special Emphasis Panel (ZRG1-IMM-J (90))
Program Officer
Davidson, Wendy F
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$210,125
Indirect Cost
$60,750
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095