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2022 Fiscal Year Research-status Report

Potential role of club cell secretory protein (CC16) in development of obese asthma: findings from a birth cohort and animal studies

Research Project

Project/Area Number 20K10425
Research InstitutionHokkaido University

Principal Investigator

Goudarzi Houman  北海道大学, 医学研究院, 准教授 (40713607)

Co-Investigator(Kenkyū-buntansha) 池田 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)
Project Period (FY) 2020-04-01 – 2024-03-31
KeywordsAsthma / Obesity / CC16 / birth cohort / adult asthma patients / Airway inflammation / T helper 2 biomarkers / Experimental studies
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.

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.

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.

Causes of Carryover

The COVID-19 pandemic reduced our research progress in terms of recruitment, support of skilled human resources, delivery of experimental materials and biomarker assays. Therefore, we moved a part of grant to the fiscal year 2023 (1,051,020 yen).
Plans in FY2023 focusing on Hokkaido birth cohort:
a)Measurement and analysis of urinary biomarkers 8-OHdG, HEL, HNE.
b)DNA extraction of CC16 genotyping: using buffy coats, we will extract DNA for further analysis. The CC16 A38G polymorphism (rs3741240) will be identified using the TaqMan system.

  • Research Products

    (13 results)

All 2023 2022 Other

All Int'l Joint Research (2 results) Journal Article (7 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 3 results) Remarks (1 results)

  • [Int'l Joint Research] Icahn School of Medicine at Mount Sinai/New York/Prof. Monica Kraft(米国)

    • Country Name
      U.S.A.
    • Counterpart Institution
      Icahn School of Medicine at Mount Sinai/New York/Prof. Monica Kraft
  • [Int'l Joint Research] Johns Hopkins University/Baltimore/Prof. Shau-ku Huang(米国)

    • Country Name
      U.S.A.
    • Counterpart Institution
      Johns Hopkins University/Baltimore/Prof. Shau-ku Huang
  • [Journal Article] Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma2023

    • Author(s)
      Goudarzi Houman、Kimura Hirokazu、Kimura Hiroki、Makita Hironi、Takimoto-Sato Michiko、Abe Yuki、Oguma Akira、Matsumoto Munehiro、Takei Nozomu、Matsumoto-Sasaki Machiko、Shimizu Kaoruko、Suzuki Masaru、Shijubo Noriharu、Huang Shau-ku、Hizawa Nobuyuki、Nishimura Masaharu、Konno Satoshi
    • Journal Title

      Respiratory Medicine

      Volume: 206 Pages: 107089~107089

    • DOI

      10.1016/j.rmed.2022.107089

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Potential determinants of T helper 2 markers and their distribution in school-aged children2023

    • Author(s)
      Goudarzi Houman、Ikeda-Araki Atsuko、Bamai Yu Ait、Ito Sachiko、Inao Tasuku、Yokota Isao、Miyashita Chihiro、Kishi Reiko、Konno Satoshi
    • Journal Title

      Allergology International

      Volume: 72 Pages: 100~106

    • DOI

      10.1016/j.alit.2022.07.009

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of obesity on CC16 and their potential role in overweight/obese asthma2023

    • Author(s)
      Goudarzi Houman、Kimura Hirokazu、Kimura Hiroki、Makita Hironi、Matsumoto Munehiro、Takei Nozomu、Nishimura Masaharu、Konno Satoshi
    • Journal Title

      Respiratory Research

      Volume: 23 Pages: s12931-02038

    • DOI

      10.1186/s12931-022-02038-1

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Further evidence for association of YKL-40 with severe asthma airway remodeling2023

    • Author(s)
      Kimura H, Shimizu K, Tanabe N, Makita H, Taniguchi N, Kimura H, Suzuki M, Abe Y, Matsumoto-Sasaki M, Oguma A, Takimoto-Sato M, Takei N, Matsumoto M, Goudarzi H, Sato S, Ono J, Izuhara K, Hirai T, Nishimura M, Konno S
    • Journal Title

      Annals of Allergy, Asthma & Immunology

      Volume: 128 Pages: 682~688.e5

    • DOI

      10.1016/j.anai.2022.03.016

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation2023

    • Author(s)
      Oguma Akira、Shimizu Kaoruko、Kimura Hirokazu、Tanabe Naoya、Sato Susumu、Yokota Isao、Takimoto-Sato Michiko、Matsumoto-Sasaki Machiko、Abe Yuki、Takei Nozomu、Goudarzi Houman、Suzuki Masaru、Makita Hironi、Hirai Toyohiro、Nishimura Masaharu、Konno Satoshi
    • Journal Title

      Allergology International

      Volume: 72 Pages: 262~270

    • DOI

      10.1016/j.alit.2022.10.007

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma2023

    • Author(s)
      Abe Yuki、Suzuki Masaru、Kimura Hirokazu、Shimizu Kaoruko、Takei Nozomu、Oguma Akira、Matsumoto-Sasaki Machiko、Goudarzi Houman、Makita Hironi、Nishimura Masaharu、Konno Satoshi
    • Journal Title

      Allergology International

      Volume: 72 Pages: 402~410

    • DOI

      10.1016/j.alit.2022.11.012

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Future career plans of medical students and the COVID‐19 pandemic: Time to recover?2022

    • Author(s)
      Goudarzi Houman、Onozawa Masahiro、Takahashi Makoto
    • Journal Title

      Journal of General and Family Medicine

      Volume: 24 Pages: 139~140

    • DOI

      10.1002/jgf2.591

    • Peer Reviewed
  • [Presentation] Effects of obesity on CC16 and their potential role in obese asthma2022

    • Author(s)
      Houman Goudarzi, Hirokazu Kimura, Hironi Makita, Mune Matsumoto, Nozomu Takei, Kaoruko Shimizu, Taku Watanabe, Masaharu Nishimura, Satoshi Konno
    • Organizer
      Japan Society for Allergology 71st Annual Meeting, 2022 October 7-9, Tokyo Japan I received the best presentation award)
    • Int'l Joint Research
  • [Presentation] Career plans and academic performance of medical students before, during, and beyond COVID-19 pandemic: Time to recover?2022

    • Author(s)
      Houman Goudarzi, Masahiro Onozawa, Makoto Takahashi
    • Organizer
      The 54th Annual meeting of the Japan Society for Medical Education, 2022 August 5-6, Gunma, Japan
    • Int'l Joint Research
  • [Presentation] Mixture exposure to plastic-related short half-life chemicals and associations with childhood asthma and allergies: The Hokkaido Study2022

    • Author(s)
      Yu Ait Bamai, Celine Guys, Michiel Bastiaensen, Atsuko Ikeda-Araki, Rahel Mesfin Ketema, Houman Goudarzi, Chihito Miyashita, Satoshi Konno, Reiko Kishi
    • Organizer
      The 34th Annual ISEE conference, 2022 September 18-21, Athens, Greece
    • Int'l Joint Research
  • [Remarks] https://www.cehs.hokudai.ac.jp/en

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Published: 2023-12-25  

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