| Project/Area Number |
20K10425
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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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| Co-Investigator(Kenkyū-buntansha) |
池田 敦子 (荒木 敦子) 北海道大学, 環境健康科学研究教育センター, 特任教授 (00619885)
今野 哲 北海道大学, 医学研究院, 教授 (20399835)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Project Status |
Granted (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Asthma / Obesity / CC16 / birth cohort / adult asthma patients / Airway inflammation / T helper 2 biomarkers / Experimental studies / Adults and children / Club cell protein (CC16) / In vivo study / Asthma and allergy / Obese asthma / Animal studies |
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| Outline of Research at the Start |
As clinical implications, CC16 levels could be applied for risk stratification for prevention of progressive airway inflammation, and optimization of asthma treatment in children especially obese individuals. With combination of epidemiological and animal studies, we may provide novel evidence that serial low CC16 concentration, as a risk factor, could be implemented in clinical setting for prevention of obese asthma (and other allergic diseases). Finally, CC16 may attract clinicians’ interest as a target of therapy in obese asthma phenotype in future studies.
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| Outline of Annual Research Achievements |
1) Adult asthma cohort): BMI was significantly and monotonously associated with reduced circulating CC16 levels in adult asthmas patients. Also, CC16 was inversely associated with sputum eosinophils and blood periostin. Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over five years of follow-up (p for trend = 0.031). 2) Animal study: The percentage of CC16-cells was reduced in the small airways of mice with obesity. In addition, serum CC16 levels were significantly lower in obese mice than in non-obese control mice. However, the serum levels of SP-A and SP-D, other products of club cells, did not vary between obese and non-obese control mice. 3) Hokkaido birth cohort: We measured circulatory CC16 in 10 year-old children of general population. BMI at age 7 and 10 was associated with reduced CC16 at age 10. Children with wheeze had a significant lower plasma CC16 (median 5.2, IQR 3.8-6.1) compared to children without wheeze (median 5.6, IQR 4.3-7.1). Plasma CC16 was inversely associated with wheeze and asthma prevalence, and 1 ng/mL increase in CC16 decreases 20% risk of wheeze in school age children (adjusted odds ratio: 0.80, 95% CI: 0.66-0.99). Also, CC16 is inversely associated with T2 phenotypes and local (FeNO) and systemic inflammation (blood eosinophils). Currently, we are focusing on the association of urinary oxidative and lipid peroxidation with CC16 and obese asthma phenotype.
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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
A)Adult asthma cohort: We have enrolled patients diagnosed with asthma by pulmonologists between 2010 and 2012 at the Hokkaido University Hospital and affiliated hospitals (n=127). Several clinical parameters were evaluated in all participants such as pulmonary function tests, biomarkers.
B)In vivo study: C57BL/6 Wild-type mice randomly were divided into two subgroups given normal chow or a high-fat diet. Blood CC16 levels and other products of club cells (SP-A and SP-D) in control mice vs. high-fat diet mice. Small airways were immunostained for CC16. We had some delays for conducting in vivo studies and receiving materials to do experiments because of the COVID-19 pandemic.
C)Hokkaido birth cohort: For allergic condition assessment, follow-up questionnaires were distributed to children aged 1, 2, 4, 7, and 10 years old, which included questions on wheeze, rhinitis, and eczema from the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires. We have measured T2 biomarkers including blood eosinophils, total serum IgE and FeNO. However, the pandemic reduced our research progress in terms of recruitment, support of skilled human resources, delivery of experimental materials and biomarker assays.
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| Strategy for Future Research Activity |
1)Adult asthma cohort: We have finished all assessment and data analysis among adult asthma patients.
2)Animal studies: All in vivo studies in this project has been completed.
3)Hokkaido birth cohort:
a)Measurement and analysis of urinary biomarkers: Previously, we measured 3 biomarkers in urinary samples of children aged 7; 8-hydroxy-2′-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL), and 4-hydroxynonenal (HNE). 8-OHdG is an oxidative stress biomarker and HEL and HNE are end products of lipid peroxidation. Recently, we have measured these three biomarkers in urinary samples of children aged 10. Currently, we are assessing association of these urinary biomarkers with CC16 and development of obese asthma phenotypes in children. We will finish such data analysis by end of this fiscal year.
b)DNA extraction of CC16 genotyping: We have collected blood samples of children at age 10. Using 200 microliter of buffy coats, we will extract DNA for further analysis. The CC16 A38G polymorphism (rs3741240) will be identified using the TaqMan system (Applied Biosystems, Foster City, CA, USA). Then, we will examine association of CC16 polymorphism with development of asthma and allergic diseases from birth to age 10. We will also assess influence of CC16 polymorphism on plasma CC16 and other asthma outcomes at age 10 by the end of this fiscal year.
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