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Use of placental microRNAs as biomarkers for placentitis

Grant number: 15/00049-5
Support Opportunities:Scholarships abroad - Research
Effective date (Start): October 01, 2015
Effective date (End): September 30, 2016
Field of knowledge:Agronomical Sciences - Veterinary Medicine - Animal Reproduction
Principal Investigator:Claudia Barbosa Fernandes
Grantee:Claudia Barbosa Fernandes
Host Investigator: Barry Allen Ball
Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Kentucky (UK), United States  


Placentitis is a common cause of abortion in late pregnant mares and poses a significant threat to fetal and neonatal viability. Several bacterial agents are commonly associated with the occurrence of placentitis with Streptococcus equi subsp. zooepidemicus predominating. Streptococci are thought to enter the uterus via the cervix through an ascending vaginal infection. Placentitis typically initiates at the cervical star and migrates cranially with a resultant inflammation, fetal infection and prostaglandin release culminating in abortion. Early detection and accurate diagnosis of placentitis are essential for effective treatment. Currentlyultrasonographic evaluation of the placenta is frequently used for diagnosis of placentitis. Advanced stages of placentitis are easilydiagnosed via ultrasonography, but earlier stages and subclinical cases of placentitis are often missed. Furthermore, ultrasonographic detection of placentitis is prone to false positive diagnoses resulting in unnecessary therapy. Due to the number of placentitis cases which go undiagnosed, it has become increasingly common to routinely treat all pregnant mares with antibiotics for 5-7 days every month during the last trimester. This practice has created the risk of developing widespread bacterial resistanceagainst antibiotics and the development of "super-bugs", despite the lack of evidence that outcomes are improving. Additional diagnostic tools are desperately needed to accurately identify cases of placentitis before visible changes in placental integrity become evident upon ultrasonography. Endocrine markers in the peripheral circulation such as progestagens, estrogens, and relaxin have been suggested as indicators of placentitis. Data in support of these markers, however, are conflicting and none of the parameters is routinely used in a clinical setting at this time. We propose to investigate novel microRNA markers for placentitis and develop a diagnostic panel to detect early subclinical cases of placentitis. MicroRNAs are small (approximately 22 nucleotides), nonconding RNAs which function in RNA silencing and regulation of gene expression. MicroRNAs are present in blood and persist for much longer periods of time than to messenger RNAs. In the current study, we will evaluate the use of microRNAs that are present in the blood of pregnant mares and produced by the placenta. Our preliminary studies have demonstrated a number ofcandidate microRNAs in the blood of mares that may be useful as a means to evaluate placental status in mares, and we now propose a two part study to examine these biomarkers in more detail. First, we will examine expression of all RNAs in the placenta of mares at four, seven and ten months of pregnancy by high-throughput RNA sequencing technology. The expression of microRNAsthat demonstrate abundant expression in the placenta will also be examined in peripheral blood of pregnant mares. Second, we will examine changes in these target microRNAs in blood samples from mares with experimentally induced placentitis compared to gestationally age-matched control mares. We will also examine expression of these target microRNAs in blood samples takenfrom a large (n = 750 mares) prospective field study. In this study, blood samples were taken weekly from late gestation mares and outcomes (placentitis vs. normal foaling) were recorded. This sample set will allow us to examine changes in expression of microRNAs in mares with spontaneously occurring placentitis compared to matched control mares with normal pregnancies. This novel approach will provide new information concerning pregnancy specific expression of microRNAs in the mare and the applicationof these biomarkers as indicators of placental and pregnancy well-being in the mare. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FERNANDES, CLAUDIA B.; LOUX, SHAVAHN C.; SCOGGIN, KIRSTEN E.; SQUIRES, EDWARD L.; TROEDSSON, MATS H.; ESTELLER-VICO, ALEJANDRO; BALL, BARRY A.. Sex-steroid receptors, prostaglandin E2 receptors, and cyclooxygenase in the equine cervix during estrus, diestrus and pregnancy: Gene expression and cellular localization. Animal Reproduction Science, v. 187, p. 141-151, . (15/00049-5)
FERNANDES, C. B.; BALL, B. A.; LOUX, S. C.; BOAKARI, Y. L.; SCOGGIN, K. E.; EL-SHEIKH ALI, H.; COGLIATI, B.; ESTELLER-VICO, A.. Uterine cervix as a fundamental part of the pathogenesis of pregnancy loss associated with ascending placentitis in mares. Theriogenology, v. 145, p. 167-175, . (15/00049-5)

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