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A Bioengineering Approach to Develop a Laminar 3D Cerebellar Neuronal Circuit for Modeling Human Cerebellum

Award Number: R01NS122902
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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A Bioengineering Approach to Develop a Laminar 3D Cerebellar Neuronal Circuit for Modeling Human Cerebellum - PROJECT SUMMARY/ ABSTRACT The formation of neuronal laminae is a fundamental feature of cortical regions of the mammalian brain. This proposal aims to generate a defined 3D system of human cerebellar neurons that faithfully reproduces the native lamination of the cerebellar cortex. The cerebellum is a key area to study, as an archetypal cortical structure and as a brain region that functions both in sensory-motor control and in non-motor functions, including cognition, emotion and language. We will use two protocols in place in the Hatten Lab to differentiate the two primary classes of cerebellar neurons from human pluripotent stem cells (hPSCs) and state of the art bioengineering methods to develop a defined 3D laminar culture system (Aim 1). We will then use calcium imaging of cell-type specific genetically encoded calcium sensors to determine correlations in neuronal firing rates as a first step toward recording circuit properties of human cerebellar neurons in a 3D in vitro laminated system (Aim 2) and transcriptomic profiling against native developing tissue (Aim 3). Among cerebellar interneurons, unipolar brush cells are important modulators of the cerebellar circuit, yet no protocols are available to derive them in vitro. We will develop the first differentiation protocols to derive these glutamatergic neurons and incorporate them into laminar models (Aim 4). This research will combine the expertise of the Millen Lab in human cerebellar development with that of the Hatten Lab in generating human cerebellar neurons from hPSCs to provide the first properly stratified human cerebellar circuit for the purposes of disease modeling and drug screening.


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 = $688,366 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/9/2025	NON-COMPETING CONTINUATION	$688,366
														Subtotal = $688,366

Issue Date FY: 2024 ( Subtotal = $696,516 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/10/2024	NON-COMPETING CONTINUATION	$50,264
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/14/2024	NON-COMPETING CONTINUATION	$646,252
														Subtotal = $696,516

Issue Date FY: 2023 ( Subtotal = $610,752 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/28/2023	NON-COMPETING CONTINUATION	$610,752
														Subtotal = $610,752

Issue Date FY: 2022 ( Subtotal = $634,977 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/6/2022	NEW	$634,977
														Subtotal = $634,977

Grand Total All Awards = $2,630,611

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A Bioengineering Approach to Develop a Laminar 3D Cerebellar Neuronal Circuit for Modeling Human Cerebellum

Award Number: R01NS122902

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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