Assay of chemicals for Parkinson’s toxicity in human iPSC-derived neurons

化学物质对人类 iPSC 衍生神经元帕金森毒性的测定

基本信息

批准号：
9020156
负责人：
PATRICK M MCDONOUGH
金额：
$ 22.49万
依托单位：
VALA SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020156
关键词：
Accounting Affect Age Alzheimer&apos s Disease Apoptotic Back Behavior Biological Assay Biological Markers Brain Calcium Cell Line Cell physiology Cells Cessation of life Chemicals Cognition Companions Dementia Development Disease Environment European Family history of Fluo 4 Generations Goals Government Agencies Health Herbicides Human Incidence Inherited Insecticides Label Leg Limb structure Link Methods Microscope Midbrain structure Mitochondria Modeling Moods Motor Mutation National Institute of Environmental Health Sciences National Toxicology Program Nerve Degeneration Neurodegenerative Disorders Neurons Nitric Oxide Nitrogen Nitrogen Oxides Oxygen Parkinson Disease Parkinson&apos s Disease Pathway Pathology Patients Pesticides Pharmaceutical Preparations Phase Population Prevalence Production Proteins Protocols documentation Provider Research Research Personnel Risk Robotics Sampling Science Skin Small Business Innovation Research Grant Solvents Stem cells Structure Substantia nigra structure Superoxides Symptoms Synapses Testing Toxic Environmental Substances Toxic effect Toxicity Tests Toxin Tremor United States Environmental Protection Agency Work Xenobiotics alpha synuclein arm base beta pleated sheet dopaminergic neuron early onset genome editing high throughput screening induced pluripotent stem cell interest male men mitochondrial dysfunction pars compacta programs protein misfolding protein structure public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the 2nd most common neurodegenerative affliction, affecting approx. 1 % of the human population. The symptoms of PD include tremors in motor function of limbs, due to progressive death of dopaminergic neurons in the brain. While certain forms of PD are inherited, it is clear that environmental toxins, including pesticides, and, likely, industrial solvents, contribute to PD, but the pathways via which this occurs are incompletely understood. α -Synuclein (α-Syn), a protein of unknown function, participates in PD pathology, likely due to mis-folding, aggregation, and toxicity to mitochondrial function. Further, environmental toxins, linked to PD, also inhibit mitochondrial function. A mutation in α-Syn (A53T) has been identified which causes an early-onset of PD. Induced pluripotent stem cells (iPSCs) have been prepared from a subject harboring the α-Syn A53T mutation, and dopaminergic neurons, derived from these iPSCs display increased PD-related responses to pesticides, compared to isogenic control iPSC cells. The goal of this Phase I SBIR project will be to develop a high throughput screen to test environmental toxins for their ability to increase the risk of PD, using iPSC-derived dopaminergic neurons harboring the A53T mutation. To identify the biomarkers that will provide the best indication of PD-related pathologies, we will test pesticides on these neurons and quantify effects on synaptic structures, mitochondria, and the generation of reactive oxygen and nitrogen species. Customers for the assay include government agencies, such as the US EPA. Vala Sciences Inc. specializes in developing cell-based assays relevant to environmental toxicity, and is an assay provider for the EPA ToxCast program. The Phase II goals will be to further refine and expand the capability of the assays that can be done with these neurons.