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Control of pituitary cell plasticity through regulated mRNA translation

Award Number: R01HD093461
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Control of pituitary cell plasticity through regulated mRNA translation - SUMMARY The anterior pituitary functions as the endocrine core of the organism, regulating hormonal synthesis and secretion to effect adaption to changing metabolic and reproductive needs. Deficiencies of pituitary-derived hormones, due to genetic causes, head injury, under or over-nutrition, or as a consequence of pituitary cancer treatment cause severe morbidity. The cells of the anterior pituitary have been long known to possess remarkable plasticity of fate suggesting the presence of stem cell-like cell populations. However, whether stem cells do indeed contribute to cell plasticity and pituitary recovery and the underlying mechanisms that control pituitary cell plasticity in response to pituitary injury, changing hormonal demands or tumor progression have not been established. The mRNA translation control protein, Musashi, has been shown to plays a critical role in mediating physiological and pathological stem cell function in many tissue types. Musashi mediates stem cell self renewal by repressing translation of target mRNAs that encode proteins required for cell cycle inhibition and cell differentiation. Our data indicate that Musashi is broadly expressed in the adult anterior pituitary in non-stem cell populations, as well as in pituitary stem cells. The overall objective of this application is to assess the role of regulated mRNA translation in general, and the Musashi protein specifically, in mediating adaptive changes of cell fate in the pituitary. The central hypothesis is that Musashi controls both pituitary stem/progenitor cell differentiation and also plasticity of hormone producing cells in the adult pituitary. Specifically, studies for Aim 1 will use both in vivo mouse models and cell culture approaches to test the hypothesis that Musashi regulates cell plasticity during tissue regeneration as well as developmental pituitary stem/progenitor cell function. Studies for Aim 2 will use unbiased polysome-based, RNA-sequencing approaches to test the hypothesis that Musashi has gender-specific mRNA targets and RNA-targeting mechanisms that control cell fate decisions in stem/progenitor cells and in adaptive responses of adult hormone-producing cell populations. The findings from this study will fully inform the field about the role of Musashi activity and mRNA translation in the control of pituitary cell plasticity and stem/progenitor cell function. Furthermore, these proposed studies relate to therapeutic approaches for endocrine and metabolic diseases, specifically caused by pituitary deficiencies. As hormone replacement strategies do not fully mimic physiological pulsatile secretion regimes, studies that promote regeneration of missing endocrine cell lineages would be a significant clinical improvement. This will positively impact gender-appropriate treatment paradigms for combined pituitary hormone deficiency, metabolic disease and pituitary tissue repair after head injury.


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 = -$27,694 )
2026	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	5	12/16/2025	NON-COMPETING CONTINUATION	-$27,694
														Subtotal = -$27,694

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	5	6/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $601,442 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	5	7/1/2022	NON-COMPETING CONTINUATION	$601,442
														Subtotal = $601,442

Issue Date FY: 2021 ( Subtotal = $601,442 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	4	7/3/2021	NON-COMPETING CONTINUATION	$601,442
														Subtotal = $601,442

Issue Date FY: 2020 ( Subtotal = $640,717 )
2020	2020	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	3	6/25/2020	NON-COMPETING CONTINUATION	$640,717
														Subtotal = $640,717

Issue Date FY: 2019 ( Subtotal = $644,333 )
2019	2019	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	2	6/28/2019	NON-COMPETING CONTINUATION	$644,333
														Subtotal = $644,333

Issue Date FY: 2018 ( Subtotal = $639,650 )
2018	2018	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Child Health and Human Development Extramural Research	000	1	8/29/2018	NEW	$639,650
														Subtotal = $639,650

Grand Total All Awards = $3,099,890

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Control of pituitary cell plasticity through regulated mRNA translation

Award Number: R01HD093461

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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