The advent of next generation sequencing (NGS) technologies has made it possible to identify the full spectrum of genetic variations in single individuals. This has made it possible to identify rare variants that contribute to human genetic diseases. However, this has quickly created a need for mechanisms to prove or demonstrate that the candidate genes are causal. One mechanism to begin to understand specific genetic variations in the context of the pathophysiology of PD is to identify the impact that changes in the expression of the candidate genes have on key cellular pathways, molecular functions and regulatory networks, so called pathway analysis. By examining the effect that the knockout or knockdown of specific candidate genes have on the transcriptome, we can begin to identify the key pathways responsible for the disease phenotype. To that end, an integrated, multi-organism disease modeling core has been established to bring together expertise in yeast, zebrafish and induced pluripotent stem cells (IPSCs) modeling. Each model organism in the core represents a different level of complexity and can be used to better understand different aspects of the pathology of PD. This core will facilitate the rapid identification of the most appropriate models for examining the impact that loss of function of specific genes (derived from Project 1 and 3) and non-coding RNAs (Project 2) have on the transcriptome (analyzed in Core C). Knockdown or knockout models of the specific candidate genes will be developed in the appropriate organisms to provide the biological material (total RNA) for transcriptome analysis. In addition to providing total RNA from the knockout/knockdown cells and tissues (and control cells and tissues), this core will generate important reagents (morpholinos, shRNAs, yeast knock strains and iPSCs) for future functional studies into the pathology of PD for members of the UM Udall Center, as well as, other Udall Centers and PD investigators.
The pace at which genetic variations can be identified has rapidly accelerated due to the advent of high content DNA sequencing technologies. By examining changes in candidate gene expression across several organisms simultaneously, we hope to gain a better understanding of PD pathology.
|Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:|
|Barbier, E; Johnstone, A L; Khomtchouk, B B et al. (2017) Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Mol Psychiatry 22:1746-1758|
|Noyce, Alastair J; Kia, Demis A; Hemani, Gibran et al. (2017) Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study. PLoS Med 14:e1002314|
|Wahlestedt, Claes (2017) Emerging Epigenetic Therapies in Neuroscience: Focus on Bromodomain-Containing Drug Targets. Neuropsychopharmacology 42:374|
|Belle, Kinsley; Shabazz, Francelethia S; Nuytemans, Karen et al. (2017) Generation of disease-specific autopsy-confirmed iPSCs lines from postmortem isolated Peripheral Blood Mononuclear Cells. Neurosci Lett 637:201-206|
|Giri, Anamika; Mok, Kin Y; Jansen, Iris et al. (2017) Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. Neurobiol Aging 50:167.e11-167.e13|
|Heilig, M; Barbier, E; Johnstone, A L et al. (2017) Reprogramming of mPFC transcriptome and function in alcohol dependence. Genes Brain Behav 16:86-100|
|Khorkova, Olga; Wahlestedt, Claes (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35:249-263|
|Wang, Xin; Li, Nuomin; Xiong, Nian et al. (2017) Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease. Mol Neurobiol 54:2878-2888|
|Jansen, Iris E; Ye, Hui; Heetveld, Sasja et al. (2017) Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol 18:22|
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