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Human stem cell derived forebrain model to study persistent neurotoxic effects of trans-placental developmental exposures to environmental pollutants

Award Number: K99ES036290
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Human stem cell derived forebrain model to study persistent neurotoxic effects of trans-placental developmental exposures to environmental pollutants - PROJECT SUMMARY The goal of this K99/R00 project is to provide training to independence and enable the PI to test the hypothesis that maternal-fetal exposures to environmental contaminants during early stages of fetal brain development render the mature nervous system more susceptible to Alzheimer’s Disease and related dementia (ADRD). Pregnant women are exposed to a large number of environmental contaminants in their daily life. Though the placental-fetal barrier protects the fetus from most harm, some chemicals cross the barrier and can negatively impact fetal development. The ‘Developmental Origins of Health and Disease’ hypothesis states that developmental exposures are a trigger for life-long persistent effects, increasing the risk and susceptibility to later-life age-related neurodegenerative diseases such as ADRD. These early-life exposures could permanently change the homeostatic state of the nervous system in a way that seemingly retains normal structural development but persistently alters function and disease-risk. We propose to develop an in vitro placental barrier linked to human induced pluripotent stem cells (hiPSCs) developing into forebrain neurons. The PI will assess whether exposures found in cord blood can cross this in vitro barrier using mass spectrometry. Then, we will study whether selected compounds (heavy metal, pesticide, plasticizer) induce a persistently altered homeostatic state in developing neurons at early age using imaging techniques as well as assessment of functional outcomes (through micro-electrode array recordings) and genetic and metabolic outcomes (using single-cell RNA sequencing). Finally, the PI will combine both models and develop an integrated placental-barrier – forebrain model and expose to selected compounds. Exposed cultures will be matured and persistency will be assessed again. Findings will be compared between different culture ages and different classes of compounds to develop persistency signatures and get better understanding on how different classes of compounds induce this neurological health risk state. Completing this study will advance the PI’s training in important new directions that are enabled by the expertise of their mentors and collaborators and will help the PI reach their goal of becoming an independent scientist. The team of mentors and collaborators is composed of experts in the following fields of: placental biology and barrier modelling, exposomics, physiology of healthy brain aging, bioinformatics and statistics, and neuro(epi)genetics. In collaboration with mentors, the PI will develop critical skills that are required for a successful transition into a position as independent academic researcher in neuro- and reproductive toxicology. This training will be accomplished through a focused development plan consisting of didactic courses, close collaboration with mentors and collaborators. At the conclusion of this proposal, the PI will have developed a human stem cell derived forebrain model to study persistent neurotoxic effects of trans- placental developmental exposures to environmental pollutants.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $125,694 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Environmental Health	000	2	3/27/2025	NON-COMPETING CONTINUATION	$125,694
														Subtotal = $125,694

Issue Date FY: 2024 ( Subtotal = $125,694 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Environmental Health	000	1	4/10/2024	NEW	$125,694
														Subtotal = $125,694

Grand Total All Awards = $251,388

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Human stem cell derived forebrain model to study persistent neurotoxic effects of trans-placental developmental exposures to environmental pollutants

Award Number: K99ES036290

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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