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Gag-like Proteins in exosome-mediated Neural Development and Fetal Alcohol Spectrum Disorders

Award Number: F30AA027698
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Gag-like Proteins in exosome-mediated Neural Development and Fetal Alcohol Spectrum Disorders - Project Summary Prenatal alcohol exposure (PAE) can result in a collection of brain-based disabilities termed Fetal Alcohol Spectrum Disorders (FASD). FASDs are estimated to affect ~1-5% of school-aged children in the US. While sociocultural factors make PAE difficult to prevent, FASD may be prevented by early interventions. The proposed studies, aimed at identifying novel, alcohol-sensitive brain growth control mechanisms mediated by a family of Gag-Like Proteins (GLPs), may uncover new ways to minimize effects of PAE. GLPs are genomic remnants of ancient retroviral infections that have since been adapted for utilization in the host organism. Some have evolved to control transcriptional regulatory networks in embryonic stem cells, whereas others like Arc facilitate plasticity in differentiated neurons, and have been hypothesized to mediate some cognitive deficits observed in neurodevelopmental disorders like Angelman’s syndrome. Arc has also recently been identified as a capsid forming protein capable of transporting its own mRNA in exosomes between neural cells, reminiscent of its Gag origin. Other GLPs may also retain functional aspects of Gag, such as the ability to interact with mRNAs and to self-target for membrane bound export. These data raise the exciting possibility that GLPs may facilitate intercellular transfer of RNAs and therefore serve as a means for programming the development and maturation of neural stem cell ensembles. Preliminary data indicate that expression of two GLPs (PEG10 and PNMA2) are selectively induced in fetal neural stem cells, following alcohol exposure. The overarching hypotheses are that these GLPs, through both intracellular mechanisms and exosome-mediated intercellular communication, control neural stem cell renewal and facilitate neurogenesis, and that perturbations in GLP expression due to alcohol exposure will result in loss of stem cell renewal and diminished neurogenesis. The immediate goal will be to identify RNA and protein partners of GLPs PEG10 and PNMA2 which mediate ethanol-effects on neural differentiation and development. Aim 1: Determine the intracellular role of Gag-like proteins PEG10 and PNMA2 in the basal and ethanol influenced differentiation of neural stem cells and neural development. Aim 2: Determine the extracellular role of PEG10 and other Gag-like proteins present in exosomes in intercellular communication and coordination of neural development under basal and ethanol conditions. Aim 3: Determine the in vivo interaction between Gag-like proteins and PAE on fetal neural development. These studies are expected to uncover novel GLP mediators of differentiation that may be manipulated in exosomes to control self-renewal and maturation of neural stem cell ensembles and to minimize effects of PAE on early neural development. This training plan’s focus on disrupting the connection between PAE and FASD integrates well with a career goal to become a pediatrician-scientist with a focus on developmental disabilities.


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 = -$10,432 )
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	001	5	3/25/2025	NON-COMPETING CONTINUATION	-$3,646
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	000	5	1/17/2025	NON-COMPETING CONTINUATION	-$6,786
														Subtotal = -$10,432

Issue Date FY: 2023 ( Subtotal = $42,216 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	000	5	7/7/2023	NON-COMPETING CONTINUATION	$42,216
														Subtotal = $42,216

Issue Date FY: 2022 ( Subtotal = $41,283 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Alcohol Research Programs	000	4	7/22/2022	NON-COMPETING CONTINUATION	$41,283
														Subtotal = $41,283

Issue Date FY: 2021 ( Subtotal = $34,703 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Alcohol Research Programs	000	3	8/2/2021	NON-COMPETING CONTINUATION	$34,703
														Subtotal = $34,703

Issue Date FY: 2020 ( Subtotal = $33,965 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Alcohol Research Programs	000	2	7/28/2020	NON-COMPETING CONTINUATION	$33,965
														Subtotal = $33,965

Issue Date FY: 2019 ( Subtotal = $33,250 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Alcohol Research Programs	000	1	9/10/2019	NEW	$33,250
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Alcohol Research Programs	001	1	9/10/2019	NEW	$0
														Subtotal = $33,250

Grand Total All Awards = $174,985

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Gag-like Proteins in exosome-mediated Neural Development and Fetal Alcohol Spectrum Disorders

Award Number: F30AA027698

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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