Mechanistic Determinants of Dietary Polyphenol Bioactivity in Bone

膳食多酚在骨中生物活性的机制决定因素

基本信息

  • 批准号:
    10303242
  • 负责人:
  • 金额:
    $ 21.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-21 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT An exponential increase in sales of curcumin-containing turmeric dietary supplements (DS), now the top selling botanical DS in the United States, has been associated with a marked increase in turmeric DS usage by Americans for the treatment of chronic musculoskeletal conditions, such as rheumatoid arthritis (30% prevalence). Scientifically, however, it has been difficult to reconcile in vivo evidence of bone protective effects of curcumin in humans and rodents with pharmacokinetic data demonstrating barely detectable circulating levels of aglycone curcumin following curcumin ingestion, due to its rapid conjugation by intestine and liver to form curcumin glucuronide, a major circulating metabolite shown to be largely inactive. Recent work by our laboratory has shed light on this process, demonstrating high activity levels of enzymatic deconjugation of curcumin glucuronide within bone to form bioactive aglycone in concentrations similar to those required in vitro to inhibit bone-resorbing osteoclast formation, a key driver of bone loss in all major bone diseases, including osteoporosis. Because glucuronidation is a common metabolic fate for many bone-protective dietary polyphenols, the primary goal of this project is to determine whether bone-protective polyphenol bioactivity is similarly dependent on ß- glucuronidase (GUSB), the enzyme required for the deconjugation of glucuronides of curcumin and other bone protective dietary polyphenols, such as quercetin, within bone. This question has great clinical relevance since GUSB expression is highly variable in human populations. Experiments will utilize a model of post-menopausal bone loss (ovariectomized [OVX] mice), mice with defects in GUSB activity and/or processing, and supplementation with a FDA-approved GUSB enzyme to assess the GUSB-dependence of bone preservation in OVX mice in response to curcumin or quercetin treatment. An investigation of the relative importance of extracellular (e.g. secreted) vs. intracellular GUSB-mediated deconjugation of dietary polyphenol glucuronides, a key question when assessing relevant enzyme phenotypes and replacement therapies in humans, will also be addressed. Given recent clinical reports of turmeric dietary supplement-associated hepatotoxicity, effects of GUSB phenotypes on liver function in curcumin-treated mice will be a secondary outcome. Our collaborative investigative team is well poised to address these research questions. Proof of concept data obtained here will be impactful, challenging our understanding and supporting new research regarding the role of enzyme phenotypes in maintaining bone health in response to dietary polyphenols, and opening new avenues for personalized approaches to promote the healthspan of our aging US population.
摘要

项目成果

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JANET L FUNK其他文献

JANET L FUNK的其他文献

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{{ truncateString('JANET L FUNK', 18)}}的其他基金

Mechanistic Determinants of Dietary Polyphenol Bioactivity in Bone
膳食多酚在骨中生物活性的机制决定因素
  • 批准号:
    10435568
  • 财政年份:
    2021
  • 资助金额:
    $ 21.21万
  • 项目类别:
Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis
利用肿瘤微环境阻止乳腺癌骨转移
  • 批准号:
    8902058
  • 财政年份:
    2014
  • 资助金额:
    $ 21.21万
  • 项目类别:
Isolation and Characterization of ER+ Breast Cancer Cells with High Bone Metastat
具有高骨转移的 ER 乳腺癌细胞的分离和表征
  • 批准号:
    8883438
  • 财政年份:
    2014
  • 资助金额:
    $ 21.21万
  • 项目类别:
Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis
利用肿瘤微环境阻止乳腺癌骨转移
  • 批准号:
    8759032
  • 财政年份:
    2014
  • 资助金额:
    $ 21.21万
  • 项目类别:
Isolation and Characterization of ER+ Breast Cancer Cells with High Bone Metastat
具有高骨转移的 ER 乳腺癌细胞的分离和表征
  • 批准号:
    8771595
  • 财政年份:
    2014
  • 资助金额:
    $ 21.21万
  • 项目类别:
Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis
利用肿瘤微环境阻止乳腺癌骨转移
  • 批准号:
    9117436
  • 财政年份:
    2014
  • 资助金额:
    $ 21.21万
  • 项目类别:
Curcuma longa L. in Rheumatoid Arthritis (CLaRA): Clinical Planning Study
姜黄在类风湿性关节炎 (CLaRA) 中的应用:临床规划研究
  • 批准号:
    8859531
  • 财政年份:
    2013
  • 资助金额:
    $ 21.21万
  • 项目类别:
Curcuma longa L. in Rheumatoid Arthritis (CLaRA): Clinical Planning Study
姜黄在类风湿性关节炎 (CLaRA) 中的应用:临床规划研究
  • 批准号:
    8490129
  • 财政年份:
    2013
  • 资助金额:
    $ 21.21万
  • 项目类别:
Curcuma longa L. in Rheumatoid Arthritis (CLaRA): Clinical Planning Study
姜黄在类风湿性关节炎 (CLaRA) 中的应用:临床规划研究
  • 批准号:
    8723741
  • 财政年份:
    2013
  • 资助金额:
    $ 21.21万
  • 项目类别:
Identification of Natural Product Inhibitors of Breast Cancer Bone Metastasis
乳腺癌骨转移天然产物抑制剂的鉴定
  • 批准号:
    7990371
  • 财政年份:
    2010
  • 资助金额:
    $ 21.21万
  • 项目类别:

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