PDGENNI · Gene-Environment Interactions in the Etiopathogenesis of Parkinson's Disease: Role of Inflammation
FP7 — People (Marie Curie Actions)
- Duration
- 2012-07-01 → 2016-06-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Gene-Environment Interactions in the Etiopathogenesis of Parkinson's Disease: Role of Inflammation
1. Background and Objectives The overall goal of our research program is to elucidate the role of the immune system in Parkinson's disease (PD). PD is the most common movement disorder with a dramatic impact on the individuals, their families and society. PD has long been considered a disorder that primarily affects the brain. However, multiple mechanisms, both systemic and within the central nervous system, interact and contribute to its onset and progression. This research proposal aims at elucidating the role of inflammation in the initiation of PD. The specific aims that are being addressed are to determine the role of inflammation in neurodegeneration and whether inflammation and genetic vulnerability interact and contribute to neurodegeneration in PD. We focus on the commonest form of PD caused by mutations in the Leucine-Rich Repeat Kinase (LRRK2) gene. Elucidating how genetic vulnerability and inflammation interact and trigger neuronal dysfunction is of paramount interest as this knowledge can provide novel pathogenetic pathways and therapeutic targets. 2. Tasks Performed and Main Results Achieved To address the role of the interaction between genetic vulnerability and inflammation and the non cell-autonomous role of LRRK2, we have generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying LRRK2 mutations as well as isogenic controls and LRRK2 knock out (KO) iPSCs by genome-editing techniques. To study the non-cell autonomous role of LRRK2 we have differentiated pluripotent stem cells into monocytes and macrophages. Main achievements of the project are: 1. Established iPSCs from healthy controls and LRRK2-PD patients (G2019S, R1441C, I2020T) 2. Generation of engineered human iPSCs (isogenic gene corrected controls, LRRK2 KO and LRRK2 SF-TAP Tag iPSCs by genome-editing techniques) 3. Establishment of protocols to differentiate induced pluripotent stem cells into monocytes and macrophages 4. Establishment of inflammation-dependent signaling in iPSC-derived LRRK2 mutant neurons and iPSC-derived monocytes-macrophages. 3. Prospects of Research Career and Re-Integration of the Fellow During the second half of the Career Integration Grant, Dr. Deleidi has consolidated scientific qualities acquired in her post-doctoral experience in the field of neurogenetics and transferred knowledge and expertise to the host institution in immunology and cell biology. Dr. Deleidi has obtained intramural and extramural funding as Principal Investigator. In addition, she has been teaching at the "Molecular and Cellular Neuroscience" Graduate School (University of Tübingen). In March 2016 Dr Deleidi has been awarded a Helmholtz Group Leader award and has been appointed as Group Leader at the German Center for Neurodegenerative Diseases in Tübingen on a 5-year tenure track position. She started her independent group that is composed of 1 post-doctoral fellow, 4 PhD students, and two research assistants. In June 2016, Dr Deleidi has been appointed as Junior Professor for Molecular Mechanisms of Neurodegeneration at the department of Neurology, Faculty of Medicine, University of Tübingen. Therefore, the Career Integration Grant has fulfilled the objective to contribute to the re-integration of Dr. Deleidi and her career development as independent scientist.
Data: CORDIS, © European Union
Project objective
Parkinson's disease (PD) is a relentlessly progressive disease characterized clinically by bradykinesia, rigidity, and resting tremor. Clinical manifestations of PD are not apparent until 80~85% of neurons in the substantia nigra pars compacta (SNc) have degenerated and striatal dopamine (DA) levels are depleted by 60~80%. At the time of diagnosis, the therapeutic window and the potential to intervene are therefore greatly reduced. Thus, there is an urgent need to understand better the pathogenetic basis of PD so that effective early neuroprotective therapies can be developed. There are many diverse genetic and age-associated risk factors for developing PD. Converging evidence, including the reduced risk for PD among long-term users of nonsteroidal anti-inflammatory drugs, strongly supports the role of inflammation in PD pathogenesis.The current research proposal aims to define the role of inflammation in the etiopathogenesis of sporadic and familial PD. By the means of a series of novel transgenic mice, we will dissect the role of different immune cells subsets in the initiation of neuron dysfunction and degeneration. To investigate whether genetic vulnerability combined with inflammation could underlie the patterns of neuron degeneration seen in PD, we will focus on the commonest form of hereditary PD which relates to mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene. Induced pluripotent stem cells (iPSC) generated from skin cells of LRRK2-PD patients, and novel transgenic mice overexpressing human LRRK2 in specific neuronal and immune cell populations, will allow us to investigate the non-cell autonomous mechanisms involved in the disease onset.Such in vivo and in vitro models of sporadic and hereditary PD provide promising experimental situations in which to investigate the subtle changes of the preclinical stages of the disease, as well as the identification of early disease biomarkers and potential new therapeutic agents.
Original text from CORDIS.
Participants
- DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV · BonnCoordinatorGermany
Links
Data: CORDIS, © European Union