Rajesh C. Miranda, PhD
Department of Neuroscience &
Interdisciplinary Program in Neuroscience (TAMU/TAMHSC)
8447 Riverside Pkwy
4106 Medical Research and Education Building
Bryan, TX 77807-3260
Fetal brain development, stem cells, microRNAs and teratology
- Fetal brain development: During the second and third trimester, the fetal brain grows at an enormous rate to generate the billions of neurons and glial cells of the brain and spinal cord. A thin layer of neural stem cells in the walls of the brain’s ventricles supports this enormous growth requirement. Our laboratory is interested in understanding the biological steps that transform uncommitted stem cells into neurons or a glial cells. To address this question, our laboratory has begun to focus on understanding the roles of a non-protein coding RNA molecules, in particular microRNAs.
- MicroRNAs: The world of non-coding RNA (Ribonucleic acid) molecules represents a paradigm shift in biology, away from the central dogma of biology which places RNA molecules as mere messengers between DNA and protein synthesis. However, more than 90% of the RNA molecules made by a cell are not destined to be translated into proteins. Instead, these evolutionary ancient molecules can do many things that proteins themselves can do, i.e., act as enzymes, signaling molecules and transcription factors for example. MicroRNAs are small non-coding RNAs, whose function is to regulate the expression of large networks of genes, to shape cell fate. Our laboratory is very interested in identifying key microRNAs that control the transformation of stem cells into neurons. These types of microRNAs will be important candidate molecules in the emerging arena of RNA therapies.
- Teratology: The maternal-fetal environment is complex, and can include a variety of toxic agents that can damage the fetus. Alcohol is a particularly damaging agent for the fetus, and maternal alcohol consumption during pregnancy is the leading cause of mental retardation and birth defects in the Unites States. Our laboratory works on the hypothesis that the process of stem cell transformation opens up a window of vulnerability to the external environment, and to drugs of abuse, like alcohol. We have found that alcohol promotes stem cell maturation, and consequent depletion. This alcohol sensitivity is mediated by a small group of microRNAs like miR335, miR153, miR21 and miR9. We are currently investigating what role these ‘teratogen-sensitive microRNAs’ play in fetal brain growth, and the spatial patterning of the emerging forebrain. We hypothesize that these types of microRNAs will play a key role in recruiting residual stem cells in both the developing and adult brain to stimulate the brain’s intrinsic regenerative capacity.
Cell biological techniques for neural stem cell isolation, renewal and manipulation. General molecular biology, immunological and microscopy techniques, genomics and microarray analyses, microRNA analyses, flow cytometry, bio-informatics and statistical modeling.
I also participate as a member of the 'training faculty' for the Texas Consortium in Behavioral Neuroscience.
- Bake S, Gardner R, Tingling JD, Miranda RC, Sohrabji F. Fetal Alcohol Exposure Alters Blood Flow and Neurological Responses to Transient Cerebral Ischemia in Adult Mice. Alcohol Clin Exp Res. 2017 Jan; 41 (1) :117-127.
- Bakhireva LN, Sharkis J, Shrestha S, Miranda-Sohrabji TJ, Williams S, Miranda RC. Prevalence of Prenatal Alcohol Exposure in the State of Texas As Assessed by Phosphatidylethanol in Newborn Dried Blood Spot Specimens. Alcohol Clin Exp Res. 2017 May;41 (5):1004-1011.
- Burrowes SG, Salem NA, Tseng AM, Balaraman S, Pinson MR, Garcia C, Miranda RC. The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex inhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus. Alcohol. 2017 May;60:149-158.
- Balaraman S, Schafer JJ, Tsend AM, Wertelecki W, Yevtushok L, Zymak-Zakutnya N, Chambers CD, Miranda RC. Plasma miRNA Profiles in Pregnant Women Predict Infant Outcomes following Prenatal Alcohol Exposure. PLoS One. 2016 Nov 9;11 (11): e0165081.
- Tsai PC, Bake S, Balaraman S, Rawlings J, Holgate RR, Dubois D, Miranda RC. MiR-153 targets the nuclear factor-1 family and protects against teratogenic effects of ethanol exposure in fetal neural stem cells. Biol Open. 2014 Jul 25; 3 (8): 741-58.
- Bake S, Tingling J, Miranda RC (2012) Ethanol exposure during pregnancy persistently attenuates cranially-directed blood flow in the developing fetus: Evidence from ultrasound imaging in a murine second trimester equivalent model. Alcohol Clin Exp Res. May;36(5):748-58. PMCID: PMC3297711
- Balaraman S, Winzer-Serhan UH, Miranda RC (2012) Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells. Alcohol Clin Exp Res. Oct;36(10):1669-77. PMCID: PMC3390449
- Sathyan P, Golden, HB, Miranda RC (2007) Competing interactions between microRNAs determine neural progenitor survival and proliferation following ethanol exposure: Evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium. Journal of Neuroscience Aug 8;27(32):8546-57. PMCID: PMC2915840
- Santillano DR, Kumar LK, Prock TL, Tingling J, Miranda RC (2005) Ethanol induces cell-cycle activity and reduces stem cell heterogeneity in cerebral cortical neuroepithelial precursors. Biomed Central: Neuroscience 6:59. PMCID: PMC1249578