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Dissecting the role of IER3IP1 in neurogenesis and brain malformation

Award Number: F30HD110088
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Dissecting the role of IER3IP1 in neurogenesis and brain malformation - Project Summary Primary microcephaly is a structural birth defect characterized by a significantly smaller head circumference than the mean of age and gender at birth. It is mainly linked to dysfunction of the neural progenitor cell population, resulting in reduced neurons in the cerebral cortex. Most microcephaly-causing genes are involved in mitosis and cytokinesis; however, recently, defects in secretory protein trafficking have been implicated in causing microcephaly. One of the newly identified genes that are potentially involved in protein trafficking is IER3IP1. Bi-allelic variants of IER3IP1 have been reported to cause a rare, pediatric, neurodevelopmental condition called microcephaly with simplified gyration, generalized epilepsy, and permanent neonatal diabetes syndrome (MEDS). MEDS patients present with severe congenital structural brain abnormalities, including microcephaly, ventriculomegaly, and cerebral atrophy. Prior studies on IER3IP1 suggest that its function is involved in ER to the Golgi trafficking in humans. I confirmed that the pathogenic variant blocks ER to Golgi trafficking with a GFP trafficking reporter, and the correction of IER3IP1 mutation through CRISPR/Cas9 restored the trafficking efficiency. Herein, I propose to focus on elucidating the function of IER3IP1 in neurogenesis and human brain development to understand how faulty protein trafficking leads to brain birth defects. I hypothesize that IER3IP1 regulates secretory protein trafficking during neurogenesis. I have successfully generated and characterized cortical brain organoids and 2D neuronal culture derived from MEDS patient-derived induced pluripotent stem cells and isogenic control cells to test this. Using these MEDS patient cell models, I will complete the following aims: Aim 1. What is the underlying cellular mechanism of microcephaly seen in MEDS patients with IER3IP1 p.L78P mutation? and Aim 2. Does IER3IP1 regulate the molecular trafficking of membrane receptors important in neurodevelopment? This proposal will fill the gap in our understanding of how protein trafficking regulates neurogenesis and provide insight into how abnormal protein trafficking leads to structural brain abnormalities.


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: 2026 ( Subtotal = -$2,197 )
2026	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$2,197
														Subtotal = -$2,197

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	001	2	6/3/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	2	3/13/2024	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	001	1	3/24/2023	NEW	$0
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	1	3/24/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $104,471

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Dissecting the role of IER3IP1 in neurogenesis and brain malformation

Award Number: F30HD110088

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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