Small regulatory RNAs participate in many eukaryotic cell functions, microRNAs (miRNAs), the major subclass of small regulatory RNAs in animal species, regulate gene expression post-transcriptionally by destabilizing and/or reducing the translation of specific 'target' mRNAs. Post-transcriptional gene regulation has revolutionary implications, yet very little is known of the roles played by miRNAs in neurons or neurodegenerative disease.
AIM 1 : CHARACTERIZE THE POLYRIBOSOMAL miRNP IN NEURON-LIKE CELLS. miRNA-related biochemistry is poorly understood. We hypothesize that miRNA-containing polyribosomal ribonucleoprotein complexes (miRNPs) represent the biochemical substrate for miRNA:mRNA regulation. We will partially purify the polyribosomal miRNP from Weri retinoblastoma cells, to characterize the biochemical properties and the protein components of this important particle.
AiM 2 : IDENTIFY AND CHARACTERIZE miRNA:mRNA PAIRS. Although hundreds of human miRNAs are known, most mRNA targets are unknown. We discerned """"""""rules"""""""" that govern miRNA:target mRNA interaction. Using these guidelines our bioinformatician collaborators predict mRNA targets regulated by human miRNAs. We will use cell biological tools to verify hypothesized miRNA-mRNA partners relevant to human neurological diseases.
AIM 3 : CHARACTERIZE A miRNA INTERACTION THAT MAY REGULATE THE EXPRESSION OF ALPHA-SYNUCLEIN (A-SN). On the basis of preliminary evidence, we hypothesize that an evolutionarily conserved sequence element in the 3'-untranslated region of A-SN mRNA is recognized by a specific miRNA (miR-93). A-SN protein plays a central role in some neurodegenerative diseases and its regulation by a miRNA would have important implications in neurobiology, neurodegenerative disease, and RNA biology. We will study this interaction using neuronal cell lines, as a prototype of miRNA:mRNA validation. We will also extend the analyses to human brain tissue in health and disease.
| Nelson, Peter T; Jicha, Gregory A (2015) Cerebrospinal fluid vascular endothelial growth factor. JAMA Neurol 72:502-3 |
| Ighodaro, Eseosa T; Jicha, Gregory A; Schmitt, Frederick A et al. (2015) Hippocampal Sclerosis of Aging Can Be Segmental: Two Cases and Review of the Literature. J Neuropathol Exp Neurol 74:642-52 |
| Scheff, Stephen W; Neltner, Janna H; Nelson, Peter T (2014) Is synaptic loss a unique hallmark of Alzheimer's disease? Biochem Pharmacol 88:517-28 |
| Nelson, Peter T; Schmitt, Frederick A; Lin, Yushun et al. (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134:1506-18 |
| Nelson, Peter T; Head, Elizabeth; Schmitt, Frederick A et al. (2011) Alzheimer's disease is not ""brain aging"": neuropathological, genetic, and epidemiological human studies. Acta Neuropathol 121:571-87 |
| Madathil, Sindhu K; Nelson, Peter T; Saatman, Kathryn E et al. (2011) MicroRNAs in CNS injury: potential roles and therapeutic implications. Bioessays 33:21-6 |
| Nelson, Peter T; Wang, Wang-Xia; Mao, Guogen et al. (2011) Specific sequence determinants of miR-15/107 microRNA gene group targets. Nucleic Acids Res 39:8163-72 |
| Wang, Wang-Xia; Wilfred, Bernard R; Madathil, Sindhu K et al. (2010) miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol 177:334-45 |
| Nelson, Peter T; Schmitt, Frederick A; Jicha, Gregory A et al. (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875-81 |
| Wang, Wang-Xia; Wilfred, Bernard R; Xie, Kevin et al. (2010) Individual microRNAs (miRNAs) display distinct mRNA targeting ""rules"". RNA Biol 7:373-80 |
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