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Discovery, Validation, and Mitigation of Genetic Mutations Underlying Hereditary Enamel Defects

Award Number: R01DE035445
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: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Discovery, Validation, and Mitigation of Genetic Mutations Underlying Hereditary Enamel Defects - ABSTRACT The FDA’s approval of life-changing gene and cell-integrated therapies for Sickle Cell Disease in December 2023 marked a significant milestone in improving patients’ lives and advancing precision medicine. We aspire to make similar advances possible to benefit individuals with disorders affecting teeth. Our research aims to integrate developmental and intervention genetics to advance knowledge and provide scientific premises to devise therapeutics for inherited disorders affecting teeth. Isolated or syndromic disorders affecting tooth enamel, amelogenesis imperfecta or Hereditary Enamel Defects (HED), occur at 1:700-14,000. HED is debilitating. Its associated chronic pain and hypersensitivity compromise digestive function, oral health and psychological well- being of the affected individuals. In Online Mendelian Inheritance of Man, there are more than 115 genes/conditions that exhibit enamel defects. Given the mode of inheritance and clinical features, 14 subtypes of HED can be identified. It is difficult to implement genetic classification of HED in dental education or clinical care, because of the complex phenotype and incomplete mapping of the responsible genes and variants for these conditions. Distinguishing between isolated and syndromic cases is especially difficult in early childhood, as tooth malformations are often the only symptoms apparent before systemic signs emerge. Nonetheless, early diagnosis is crucial, as prognosis is greatly influenced by the severity of systemic involvement. Establishing an accurate clinical and genetic diagnosis of HED can be transformative, offering insights into pathogenicity, disease progression, and optimal management of systemic manifestations. Advanced genomic technologies and engineered delivery strategies have expanded the possibilities of genetic interventions while well-characterized mutant mouse models and tooth organs serve as robust platforms for testing these approaches. Our objective is to leverage knowledge of normal and pathological mechanisms of enamel formation to establish scientific framework for the diagnosis and interventions of HED. Our central hypotheses are (1) using advanced human and mouse genomics and computational technologies, we can improve genetic discovery, testing, and diagnosis of HED; and (2) using validated rAAV constructs in developing tooth organs, we can tailor sustained replacement gene expression to mitigate loss-of-function mutations. To achieve our objective, we aim to: (1) create an Atlas of Genetic Disorders Affecting Teeth to facilitate genetic testing, dental genetics education, and patient diagnosis and management; (2) establish workflows for variant annotation and validation enabling ongoing gene discovery in tooth development; and (3) develop in vitro and in vivo systems for genetic intervention in specific cases where the molecular mechanisms of the defects, as well as corresponding mouse models, have been characterized. Our overarching goal is to harness emerging technologies to propel the field of dental genetics forward and to develop intervention strategies that will lay the groundwork for future therapeutic approaches for patients with hereditary enamel defects.


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 = $442,870 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Oral Diseases and Disorders Research	000	1	8/3/2026	NEW	$442,870
														Subtotal = $442,870

Grand Total All Awards = $442,870

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Discovery, Validation, and Mitigation of Genetic Mutations Underlying Hereditary Enamel Defects

Award Number: R01DE035445

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: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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