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Cellular analysis of hedgehog signaling in zebrafish tooth development

Award Number: R15DE023667
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: 03/01/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2019

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Cellular analysis of hedgehog signaling in zebrafish tooth development - ¿DESCRIPTION (provided by applicant): Intercellular communication by the hedgehog cell signaling pathway is known to be essential for human craniofacial and dental development, and the ligand protein Sonic hedgehog (Shh) has been established as a key molecule during odontogenesis. However, it is incompletely understood exactly how Shh controls the cellular mechanisms of odontogenesis and which other cell signaling pathways influence this control. The long- term goal of this research is to understand how cell signaling instructs embryonic tissues to adopt the correct morphology and organization to produce a mature tooth of the proper shape and size. The objectives of this proposal are to learn more precisely the developmental cellular phenotypes that Shh signaling controls during tooth formation and how other signaling pathways may be required for this control, by exploiting advances in genomics and imaging technologies using the zebrafish vertebrate model system. The central hypothesis guiding this proposal is that secretion of Shh from the inner dental epithelium regulates tooth size and shape by directing the movement and proliferation of cranial neural crest cells during the formation of the dental papilla, and that signaling from other pathways (EDA, FGF, and/or RA) modulates this hedgehog function. The rationale for the proposed work is that a more exact understanding of the cellular behaviors that hedgehog signaling controls during odontogenesis will provide the mechanistic information needed to target the hedgehog pathway in translational dental therapies, such as regrowing teeth de novo in humans, and maximize the chance of their success. Guided by strong preliminary data, the hypothesis will be tested by completing the following two specific aims: 1) manipulate hedgehog activity in vivo to test the role of Shh in the formation of the dental papilla and 2) Test interactions between hedgehog and other signaling pathways during odontogenesis. Under the first aim, the approach will be to spatiotemporally modulate levels of Shh activity and observe the consequent effects within tooth germs on gene expression, cell movement, cell proliferation, and tooth morphogenesis. Under the second aim, the approach will be to simultaneously manipulate levels of hedgehog signaling and those of other pathways known to be able to functionally alter zebrafish tooth development including EDA, FGF, and RA, looking for additive or synergistic effects. Preliminary data indicate that Shh may play a previously unknown, specific, and essential role in the formation of the dental papilla. This proposed research is innovative; because it will exploit the evolutionary position of zebrafish as a vertebrate as well as the experimental accessibility of this model system to quickly obtain data that would be more time consuming, costly, or even impossible to obtain in mammals. The contribution of the proposed work will be significant because it will provide new information about how hedgehog signaling specifically directs cells during their participation in tooth formation and may allow for more directed targeting of the hedgehog pathway and the cells that it controls in translational dental therapies such as human tooth regeneration.


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: 2019 ( Subtotal = $0 )
2019	2015	BOWDOIN COLLEGE	5600 COLLEGE STATION	BRUNSWICK	ME	04011	CUMBERLAND	USA	Oral Diseases and Disorders Research	000	1	5/31/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $362,392 )
2015	2015	BOWDOIN COLLEGE	5400 COLLEGE STATION	BRUNSWICK	ME	04011	CUMBERLAND	USA	Oral Diseases and Disorders Research	000	1	2/4/2015	NEW	$335,657
2015	2015	BOWDOIN COLLEGE	5400 COLLEGE STATION	BRUNSWICK	ME	04011	CUMBERLAND	USA	Oral Diseases and Disorders Research	001	1	2/5/2015	NEW	$26,735
														Subtotal = $362,392

Grand Total All Awards = $362,392

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Cellular analysis of hedgehog signaling in zebrafish tooth development

Award Number: R15DE023667

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: 03/01/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2019

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