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Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis

Award Number: R01DE029832
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis - PROJECT SUMMARY Anomalies of the face invariably require some type of therapy, corrective surgery, and close follow-up while imposing a financial and emotional burden on patients and their families. Although the analysis of human data is critical, human studies pose particular problems, not the least of which is that critical times of prenatal development are not available for study. This proposal aims to identify the developmental and molecular processes underlying mandibulofacial anomalies using mouse mutants that we identified by systematically searching the current contents of the International Mouse Phenotyping Consortium (IMPC) in response to NIH PAR-20-137 for phenotyping IMPC embryonic and perinatal lethal KO mouse lines. Micro- or retrognathia are the most common terms used to describe mandibular phenotypes in mandibulofacial dysostosis, yet the current lack of precision in diagnoses of mandibular dysmorphology does not critically consider the potentially distinct etiology of these conditions and their influence on potential sequelae of anomalies. Micrognathia describes a mandible that is absolutely reduced in size, indicating that the mandible is primarily affected, while retrognathia refers to a normally sized mandible that is placed posteriorly relative to the upper jaw. Thus, micrognathia and retrognathia, while providing similar facial profiles, are produced by different primary developmental processes and each may integrate differently with tongue and palatal development. When mandibular dysmorphology occurs with glossoptosis, respiratory obstruction, and in some cases, a cleft palate, the condition is referred to as Pierre Robin (PR). A causative pathogenesis of a sequence of developmental events has been hypothesized for PR, but few clear causal relationships between discovered mutations, dysregulated gene expression, precise cellular processes, and PR-associated anomalies are documented. To test this hypothesis, we plan a carefully coordinated and fully collaborative set of analyses of IMPC mutant mouse lines identified based on genes known to be causative for PR in humans or on the presence of PR features recorded in these mouse lines. Our in-depth phenotyping will involve: Aim 1: quantitative 3D morphologic analyses of embryos using phosphotungstic acid-enhanced micro computed tomography; Aim2: differential gene expression analysis of relevant tissues and developmental time points between mutant and unaffected littermate controls using bulk RNA-seq and spatial transcriptomics; Aim 3: histologic studies using in situ hybridization or immunohistochemistry of relevant genes, signaling pathways, cellular processes, and differentiation states to determine the cellular and molecular events giving rise to dysmorphogenesis of the mandibulofacial complex. This multi-level, systems biology approach will provide precise definitions of the localized effects of genetic variants on mandibular and associated tongue, palatal, and upper airway phenotypes to identify the developmental and molecular functions involved in their production, using mouse lines that model the phenotypes associated with these conditions.


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 = $0 )
2025	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Oral Diseases and Disorders Research	001	4	7/1/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	000	3	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $713,426 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Oral Diseases and Disorders Research	001	4	7/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$713,426
2024	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	000	3	7/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $713,426

Issue Date FY: 2023 ( Subtotal = $731,718 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	001	3	7/10/2023	NON-COMPETING CONTINUATION	$731,718
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	000	2	6/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $731,718

Issue Date FY: 2022 ( Subtotal = $724,402 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	001	2	7/11/2022	NON-COMPETING CONTINUATION	$724,402
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	10/7/2021	NEW	$0
														Subtotal = $724,402

Issue Date FY: 2021 ( Subtotal = $755,836 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	8/16/2021	NEW	$755,836
														Subtotal = $755,836

Grand Total All Awards = $2,925,382

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Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis

Award Number: R01DE029832

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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