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A screening assay for chemicals that affect the differentiation of human neural cells.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41ES026225-01
Agency Tracking Number: R41ES026225
Amount: $224,985.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIEHS
Solicitation Number: ES15-005
Solicitation Year: 2015
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-09-30
Award End Date (Contract End Date): 2016-08-31
Small Business Information
Portland, OR 97211-8052
United States
DUNS: 078667905
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (971) 533-1984
Business Contact
Phone: (971) 533-1984
Research Institution
3181 SW Sam Jackson Pk Rd
PORTLAND, OR 97239-3098
United States

 Nonprofit College or University

DESCRIPTION provided by applicant Human brain development represents a highly vulnerable time to chemical exposures because immature cells are actively undergoing differentiation into more complex cell types e g neurons astrocytes oligodendroglia to form neural circuits A major reason for this vulnerability is that neuronal differentiation requires critical time dependent changes to the epigenome i e neuroepigenetics and environmental exposures pose acute risks to the epigenomes of actively differentiating cells Significantly abnormal brain develop from epigenomic perturbation is believed to be an underlying cause of several neurological disorders including autism and schizophrenia Despite this risk however the identity of chemicals present in our environment that affect human neuronal differentiation and do so by perturbing developing epigenomes is lagging Nzumbe Inc is responding to RFA ES entitled andquot Novel Assays for Screening the Effects of Chemical Toxicants on Cell Differentiationandquot with an application to develop a screening assay to identify chemicals that interfere with the process of neural differentiation Our focus will be on chemicals that perturb epigenetic mechanisms because of their potential to stably and aberrantly affect brain development We will use markers of neuronal and glial cell differentiation to identify effects from chemical exposures Two specific aims are proposed The first aim will use human neuroprogenitor neural stem cells hNPCs derived from human iPS cells to establish time points of interest as the hNPCs differentiate into cell subtypes recapitulating normal human brain development This work will be performed with hNPCs undergoing proliferation and differentiation in well plates to facilitate automated screening Fluorescent labeled antibodies
will allow for automated screening to distinguish the different cell subtypes that arise at each time point tested and their relative proportions in the total cell population The work proposed in
aim will test the effects of five chemicals with known and suspected epigenetic activities for their ability to perturb normal differentiation as described in aim These chemicals include two
well characterized epigenetic inhibitors deoxyazacytdine and trichostatin A which inhibit DNA methylation and histone deacetylation respectively as initial controls Next we will test two
chemicals on the tox list valproic acid and Bisphenol A which can perturb epigenomes and alter brain development and a third chemical methylazoxymethanol which has clear effects on neuronal development and is both a metabolite and precursor of several chemicals on the tox list The proposed work will identify discrete time points and cell specific markers that can be
used to screen for aberrant changes in neuronal differentiation following exposures to chemicals with epigenetic activities This work will lead to a well defined assay that can be commercialized in a phase II funded program

PUBLIC HEALTH RELEVANCE The period of active neuronal differentiation is particularly sensitive to chemical exposures However screening assays for such chemicals still need to be developed The objective of this application is to develop a screening assay to identify chemicals that perturb neuronal differentiation with a focus on chemicals that do so via epigenetic activities

* Information listed above is at the time of submission. *

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