| Project/Area Number |
23K09664
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 58020:Hygiene and public health-related: including laboratory approach
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2025: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2024: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2023: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | Asthma / Obesity / Birth cohort / adult asthma cohort / CCL18 / Immune pathways / Epidemiological studies / T2 biomarkers / Obese asthma phenotype / Cohort studies / T2 inflammation / Experimental studies |
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| Outline of Research at the Start |
For the first time, we will show the effects of human CCL18 in the development of obese asthma and enhancement of Th2 inflammation in the general population of children and adult asthmatic patients. Additionally, a detailed mechanism of CCL18 regulation and the role of CCL18 in eosinophilic airway inflammation in obese asthma phenotypes will be addressed for the first time in experimental studies. This project is a collaboration between clinicians and epidemiologists, providing this opportunity to improve children's health by translating the findings from bench to bedside.
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| Outline of Annual Research Achievements |
1) Hokkaido birth cohort: An ongoing population-based cohort study that began in 2002 (n = 20,926). We have finished interviews and physical examinations of children aged 10 years (n=418) for allergic condition assessment. Parents completed the ISAAC questionnaires to assess wheeze, rhinitis, and eczema. Also, information on sociodemographic characteristics, anthropometric measures, doctor-diagnosis of asthma, and confounders from pregnancy to age 10 have been collected. We have collected biospecimens in children and measured T2 biomarkers in children, including blood eosinophils, and FeNO. We measured plasma CCL18 protein as a novel T2 biomarker at ten years of age by ELISA (R&D Systems). Because of the influence of the CCL18 genotype on CCL18 levels, we will determine CCL18 polymorphism using the TaqMan system. 2) Adult asthma cohort: We enrolled patients who were diagnosed with asthma by respiratory physicians in the Hokkaido University Hospital and 29 other affiliated hospitals and clinics. A total of 220 subjects (141 with severe asthma and 79 with mild-to-moderate asthma) underwent procedural evaluations at entry and followed each year for 6 years. We have evaluated all participants for clinical parameters, pulmonary function tests, FeNO, CT images, and biosamples. We have started data analysis to assess the effect of BMI and obesity with CCL18 in asthma patients. We found that there is a significant positive association between CCL18 and BMI in asthma patients. Also, CCL18 is associated with elevated blood eosinophils, sputum eosinophils, and FeNO as T2 biomarkers.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
1) Hokkaido Birth Cohort: Recruitment of study participants at age 10 has been completed successfully. We collected baseline characteristics of parent-child pairs without issues. Information on the allergic conditions of the children, which is the main outcome of the current study using ISAAC, was gathered with minimal missing data. All survey information has been extracted, and data input into Excel files is complete. Double checks and data cleaning have also been performed. Notably, we collected biospecimens from over 95% of the children. Given the difficulty of obtaining such samples from the general population and the initial concerns about gaining consent from parents and children, this high acceptance rate is significant. T2 biomarkers in examined children were measured with almost no missing data (only 2% of the children had missing data). The determination of CCL18 genotyping and plasma CCL18 protein levels, which are key topics of the current study among children, has been successfully performed. 2) Adult Asthma: Recruitment of participants, sample collection, pulmonary function tests, and biomarker measurements were completed as planned at the start of the project. We have begun data analysis to assess the association of obesity indices with CCL18. The examination of the association between CCL18 and T2 biomarkers has been completed, yielding promising results.
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| Strategy for Future Research Activity |
We will include experimental studies to find possible mechanism(s) of CCL18's role in the obese asthma phenotype. Our plans for the next fiscal year:
1) Hokkaido birth cohort: We will extract DNA from buffy coat samples of children at age 10 to determine genetic polymorphisms of CCL18, which could have a significant effect on circulatory CCL18 levels. We will assess such possible effects in this fiscal year. Also, we will start assessing the association of BMI and obesity with CCL18 in children. As the next step and to dig further to explore the mechanism of CCL18 in obese asthma, we will examine the association of CCL18 with T2 biomarkers in children. 2) Adult asthma cohort: According to our preliminary analysis, CCL18 is an important protein in the pathogenesis of obese asthma by enhancing T2 inflammation. We will look at the association of CCL18 with pulmonary function tests, risk of exacerbation and hospitalization with a prospective approach. We will replicate such data in an additional two cohorts in this fiscal year. As with the birth cohort, we will determine the genetic polymorphisms of CCL18 in adults as well. 3) Initiation of experimental studies: Because CCL18 is not expressed in rodents, in vivo studies are not possible for this project. We will clarify the possible upstream regulatory pathways of CCL18 using in vitro studies. We will treat THP1 cells enriched for macrophages as the main source of CCL18 in humans and treat the cells with several interleukins, adipokines, and mediators to find regulatory pathways of CCL18.
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