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Hyperglycemia Induced-miR-467 in Regulation of Inflammation in Health and Disease

Gajeton, Jasmine Joy
http://orcid.org/0000-0002-8817-1562
http://rave.ohiolink.edu/etdc/view?acc_num=case1607684190604311

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Genome-wide analyses have uncovered important roles of microRNAs in diabetes mellitus pathogenesis, including evidence suggesting a regulatory relationship between microRNAs, glucose metabolism, and inflammation. Due to their specific expression profiles, microRNAs are interesting as targets for precision medicine or as clinical biomarkers; miR expression can be fine-tuned by different stressors, adding complexity in regulation of miRNAs and its targets. Hyperglycemia (high blood glucose levels) is often a consequence of insulin resistance and obesity. It is diagnosed with a random blood glucose sample ≥ 200 mg/dL with symptoms presenting as increased thirst, weight loss, blurry vision, or polyuria. Individuals diagnosed with diabetes or obesity have low-grade systemic inflammation and predisposition for developing certain cancers, like breast cancer. Interventional studies suggest that maintaining better blood glucose control improves overall health and reduces breast cancer risk. First, we identified a differential regulation of glucose clearance: inhibiting miR-467, using an antagonist, in chow-fed mice raised insulin to levels comparable to western diet-fed mice, increased fasting blood glucose levels, inhibited glucose clearance, and increased inflammation and macrophage content in adipose tissue. Our results suggest that miR-467 normally prevents inflammation in adipose tissue in response to hyperglycemia, and targets unknown transcripts that regulate glucose and insulin levels. Interestingly, the anti-inflammatory role of miR-467 is lost in mice fed a long-term western diet (rich in fat, sugar and cholesterol): antagonist injections in western diet mice lowered insulin levels and improved glucose clearance despite elevated fasting blood glucose levels, suggesting improved sensitivity to insulin. Second, we investigated how miR-467 regulates hyperglycemia-induced inflammation and breast cancer growth, exploring its potential as a clinical biomarker. In hyperglycemic mice, miR-467 accelerated tumor growth by inducing angiogenesis and promoting tumor-associated macrophage recruitment to drive hyperglycemia-induced cancer inflammation and growth. In a small cohort of human samples, hyperglycemia increased miR-467 expression in breast tissue and plasma; tissue expression was even higher from hyperglycemic patients with breast cancer. Thus, miR-467 may be clinically useful as a non-invasive, circulating biomarker to detect breast cancer, specifically in hyperglycemic patients. Together, this work details physiological and pathological roles of hyperglycemia-induced miR-467, which regulates inflammation in tissues.
Olga Stenina-Adognravi, PhD (Advisor)
Suneel Apte, M.B.B.S., D.Phil. (Committee Chair)
Keith McCrae, MD (Committee Member)
Donna Driscoll, PhD (Committee Member)
Eugene Podrez, MD, PhD (Committee Member)
142 p.
Biomedical Research
microRNA; hyperglycemia; inflammation; insulin resistance; macrophages; breast cancer; biomarker

Recommended Citations

Citations

  • Gajeton, J. J. (2021). Hyperglycemia Induced-miR-467 in Regulation of Inflammation in Health and Disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1607684190604311

    APA Style (7th edition)

  • Gajeton, Jasmine. Hyperglycemia Induced-miR-467 in Regulation of Inflammation in Health and Disease. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1607684190604311.

    MLA Style (8th edition)

  • Gajeton, Jasmine. "Hyperglycemia Induced-miR-467 in Regulation of Inflammation in Health and Disease." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1607684190604311

    Chicago Manual of Style (17th edition)

case1607684190604311
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.