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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS050110-06
Application #
7615488
Study Section
NST-2 Subcommittee (NST)
Program Officer
Sutherland, Margaret L
Project Start
2005-04-01
Project End
2010-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$176,729
Indirect Cost
Name
University of Kentucky
Department
Pathology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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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