Influence of genotype on monocyte/microglia phenotype and function in PD Project Summary/Abstract. Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of ?-synuclein in which the dopaminergic neurons of the substantia nigra die. The innate immune system is thought to play a role in the demise of these neurons. Therefore, we hypothesized that genotypic differences in innate cells, such as infiltrating macrophages as well as resident microglia are involved in the pathophysiology of PD and, particularly, in the death of these dopamine producing cells. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 8 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in monocytes and not in T cells that represent the adaptive arm of the immune system. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to PD pathology. The principal goals of the proposed project are (1) to identify the component genes of networks perturbed by the PD susceptibility loci in myeloid cells (2) to understand their functional consequences on monocyte behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.

Public Health Relevance

Influence of genotype on monocyte/microglia phenotype and function in PD Project Narrative Relevance to public health. This project is of direct relevance to Parkinson's disease, as we are proposing to study the discovery of novel targets associated with genetic variants expressed in the innate immune system that lead to Parkinson's disease. We are examining monocytes from patients with Parkinson's disease, as well as healthy young subjects to examine the genetic variation with out the confounder of disease. We will use a systems biology approach to unravel the complexity of genome-wide association studies and identify key nodes in the networks that could serve as therapeutic targets. Our data will potentially provide a therapy to target the innate immune system contribution to Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56NS089674-01
Application #
8928814
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Sieber, Beth-Anne
Project Start
2014-09-30
Project End
2015-08-31
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$463,512
Indirect Cost
$170,702
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115