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 #
1K08NS050110-01
Application #
6849160
Study Section
NST-2 Subcommittee (NST)
Program Officer
Murphy, Diane
Project Start
2005-05-01
Project End
2006-03-31
Budget Start
2005-05-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$109,755
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Nelson, Peter T; Kiriakidou, Marianthi; Mourelatos, Zissimos et al. (2010) High-throughput experimental studies to identify miRNA targets directly, with special focus on the mammalian brain. Brain Res 1338:122-30
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

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