Project II. Long Noncoding RNAs as Epigenomic Modulators and CSF Biomarkers in Parkinson's Disease This proposal will explore the presence and differential expression of non-protein-coding RNAs (ncRNAs) in cerebrospinal fluid (CSF) and tissue samples from patients with Parkinson's disease (PD) and their relationship to the methylation status of the protein coding genes they regulate. In addition, this project will aim to develop biomarker panels in order to diagnose PD, monitor disease progression and response to treatment. The mammalian genome is subject to a vast array of transcriptional events, generating a wide spectrum of functional RNA species. These molecules range from the familiar protein-coding mRNAs to long non-coding transcripts whose diversity appears to match that of mRNAs. We hypothesize that the ncRNAs are deeply involved in PD pathophysiology, through induction of epigenetic modifications. NcRNAs may be proven helpful to explain the causes, to define novel therapeutic targets and to delineate biomarkers for PD. We will harness the power of sequencing technologies to discover novel RNAs involved in PD, in order to shed light on pathological processes and provide a basis for improved diagnosis and patient care. Recent publications have revealed an important role for dysregulation of ncRNAs in various human neuropathologies, such as Alzheimer's disease [1, 2], PD [3] and Fragile X mental retardation [4]. Our study will allow the discovery of novel ncRNAs in the CSF and brain of PD subjects and define the mechanistic role these ncRNAs play in the modification of epigenetic marks, such as CpG methylation. We will examine the RNA and protein content of CSF from PD subjects for biomarker evidence of these epigenetic changes. We strongly believe that we will be able to describe the genome wide effects of ncRNAs expression on methylation status and tie this to a practical and measurable biomarker.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071674-04
Application #
8539094
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$496,417
Indirect Cost
$172,000
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Rawlik, Konrad; Rowlatt, Amy; Tenesa, Albert (2016) Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease. Genetics 204:771-781
Lubbe, Steven J; Escott-Price, Valentina; Brice, Alexis et al. (2016) Is the MC1R variant p.R160W associated with Parkinson's? Ann Neurol 79:159-61
Nuytemans, Karen; Maldonado, Lizmarie; Ali, Aleena et al. (2016) Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants. Neurol Genet 2:e44
El Hokayem, Jimmy; Cukier, Holly N; Dykxhoorn, Derek M (2016) Blood Derived Induced Pluripotent Stem Cells (iPSCs): Benefits, Challenges and the Road Ahead. J Alzheimers Dis Parkinsonism 6:
Esanov, Rustam; Belle, Kinsley C; van Blitterswijk, Marka et al. (2016) C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol 277:171-7
Lubbe, S J; Escott-Price, V; Brice, A et al. (2016) Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. Neurobiol Aging 48:222.e1-222.e7
Hossein-Nezhad, Arash; Fatemi, Roya Pedram; Ahmad, Rili et al. (2016) Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson's Disease. J Parkinsons Dis 6:109-17
Xiong, Nian; Li, Nuomin; Martin, Eden et al. (2016) hVMAT2: A Target of Individualized Medication for Parkinson's Disease. Neurotherapeutics 13:623-34
Zeier, Zane; Esanov, Rustam; Belle, Kinsley C et al. (2015) Bromodomain inhibitors regulate the C9ORF72 locus in ALS. Exp Neurol 271:241-50
Pastori, Chiara; Kapranov, Philipp; Penas, Clara et al. (2015) The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc Natl Acad Sci U S A 112:8326-31

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