Supplement Abstract Race plays an important role in UF risk. African American women have 3?4 times higher prevalence of UFs, frequent need for surgery at younger age, higher multiplicity of fibroids lesions, and more severe manifestations and complications than Caucasian women. The etiology of this racial/ethnic disparity is still not fully understood, however recent studies suggest that etiology is ?multi-factorial?. The scope of the parent R01 grant is centered on understanding the link between vitamin D deficiency as a major risk factor for UFs growth and progression in African American compared women. Vitamin D is a well-established anti-inflammatory molecule that influence several components of host immune responses. Recent reports (not available at time of preparation of the parent R01) have shown strong link between vitamin D deficiency, and altered microbiome in the gut. Additional recent reports (also not available at time of preparation of the parent R01) and the preliminary data from our group generate unprecedented and timely opportunity for this innovative supplemental research proposal, have shown consistent variance in reproductive tract microbiome. A general shift in the microbiota from beneficial butyrate- producing bacteria towards opportunistic pathogens has been described in patients with various diseases including cancer. However, the role of vitamin D deficiency-induced alteration uterine fibroids microbiome and the potential role of this link to the pathogenesis of UF has not investigated before. We hypothesize that hypovitaminosis D may not only exacerbates DNA damage accumulation and genomic instability in MED12- mutant UFs (focus area of the parent RO1), but also modulate the gut microbiome (focus area of administrative supplement), which in turn lead to enhanced tumor progression and growth. A better characterization of changes in local reproductive tract microbiome composition and functional potential, and association with vitamin D deficiency in UF patients will facilitate the development of effective novel prevention and therapeutic strategies for this important and common disease. These very recently published reports and additional preliminary data from our group generate unprecedented and timely opportunity for this innovative supplemental research proposal.
Uterine fibroids (UFs; leiomyomas) are the most frequent tumors in women worldwide and, although benign, are nonetheless associated with significant gynecologic and reproductive dysfunction. Current treatment options are limited beyond surgery, and the development of alternative effective medical therapies will require a better understanding of the underlying molecular etiology of UFs. This proposal is impactful as it suggests a new mechanistic basis to explain UF development through a vicious cycle involving reproductive tract microbiome and inflammatory fibrosis of MED12-mutant UFs, the predominant fibroid subtype, and further offers proof of concept for therapeutic intervention in this specific genetic setting. The studies proposed herein thus address for first time to connect two overarching issues in the field: the role of endogenous uterine fibrosis microbiome and in the molecular pathogenesis of UFs.
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