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The role of rRNA transcription and ribosome biogenesis in neural crest progenitors and stem cells during embryonic and postnatal craniofacial development

Award Number: F32DE033617
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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The role of rRNA transcription and ribosome biogenesis in neural crest progenitors and stem cells during embryonic and postnatal craniofacial development - ABSTRACT Craniofacial anomalies are the most common malformations present at birth and comprise up to 1/3 of all congenital defects. Most of the craniofacial cartilage, bone and connective tissue are derived from neural crest cells (NCC), a migratory stem and progenitor cell population born during early embryogenesis. The majority of craniofacial disorders are therefore thought to be a result of disruptions in NCC development3. In order to improve the prognosis for individuals affected with craniofacial anomalies, and to develop potential preventative therapies, there is a critical need for a deeper understanding of the fundamental mechanisms that govern the formation, migration and differentiation of NCCs during craniofacial morphogenesis4. Recent work in our lab demonstrated that RNA Polymerase I (Pol I)-mediated ribosomal RNA (rRNA) transcription, which is the rate limiting step in ribosome biogenesis, is elevated in NCCs compared to other cell types5, 6. This is necessary to meet NCC’s higher protein translational requirements and underpins their high rate of proliferation, epithelial to mesenchymal transformation, and metabolically expensive migration properties5. In support of this idea, NCC- specific disruption of Pol I function leads to increased NCC death and craniofacial anomalies characteristic of congenital craniofacial disorders such as Treacher Collins syndrome and Acrofacial Dysostosis-Cincinnati type5, 7, 8. Additionally, evidence from other studies supports elevated requirements for ribosomes and translational capacity in order for stem cells to acquire new fates, suggesting that ribosome biogenesis also plays a critical role during the differentiation stage of NCC development. Based on our previous findings I hypothesize that increased rRNA transcription and ribosome biogenesis are essential for both NCC-derived progenitor and stem cell maintenance and differentiation during embryonic and also juvenile phases of craniofacial development. To test this hypothesis, I will genetically delete Polr1a, the catalytic core of Pol I, in tamoxifen-inducible global and tissue-specific mouse lines. Then through phenotypic and cellular analyses, in combination with transcriptomic and proteomic approaches, I will define the mechanisms driving the anatomical anomalies that result from disruptions in Pol I function. My results will provide new knowledge on the roles of rRNA transcription and ribosome biogenesis in craniofacial progenitor and stem cell populations during embryonic and postnatal development. The findings can potentially uncover new therapies for preventing or ameliorating ribosomopathies, and improve clinical outcomes for craniofacial patients, especially when it comes to corrective surgeries, through improved postnatal growth predictions.


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 = $84,948 )
2026	2026	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Oral Diseases and Disorders Research	000	3	2/26/2026	NON-COMPETING CONTINUATION	$83,544
2026	2026	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Oral Diseases and Disorders Research	001	3	4/15/2026	NON-COMPETING CONTINUATION	$1,404
														Subtotal = $84,948

Issue Date FY: 2025 ( Subtotal = $81,024 )
2025	2025	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Oral Diseases and Disorders Research	001	2	8/12/2025	NON-COMPETING CONTINUATION	$1,332
2025	2025	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Oral Diseases and Disorders Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$79,692
														Subtotal = $81,024

Issue Date FY: 2023 ( Subtotal = $72,592 )
2023	2023	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Oral Diseases and Disorders Research	000	1	9/21/2023	NEW	$72,592
														Subtotal = $72,592

Grand Total All Awards = $238,564

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The role of rRNA transcription and ribosome biogenesis in neural crest progenitors and stem cells during embryonic and postnatal craniofacial development

Award Number: F32DE033617

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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