Ras proteins are a family of signal switch molecules that control multiple cellular responses, including proliferation, differentiation, survival and senescence, mostly through activation of the Mitogen-Activated Protein Kinase (MAPK) cascade. The RASopathies, a newly defined group of medical genetic syndromes, are caused by alterations of the Ras/MAPK pathway. These include, among others, Noonan syndrome, neurofibromatosis 1, Costello syndrome (CS) and cardio-facio-cutaneous syndrome. Taken together, the Rasopathies are one of the largest groups of malformation syndromes known, affecting >1:1000 individuals. Using them as a model provides a unique opportunity to study the role of Ras signaling in craniofacial and bone development. CS is caused by a heterozygous de novo germline mutation in HRAS that results in a constitutively active Ras protein. As in other RASopathies, the appendicular skeleton of CS patients is frequently affected. Skeletal anomalies include low bone mass and short stature, leading to the hypothesis that activation of the Ras pathway affects bone cell function. However, apart from possible osteoclast hyperactivity, little is known about the role of Ras signaling in bone homeostasis. The craniofacial skeleton and the dentition of patients with CS and other RASopathies are also significantly affected, with severe functional and cosmetic consequences, but these phenotypes have yet to be systematically examined. The overall goal of the proposed research is to understand how craniofacial bone development is affected by germline Ras dysregulation, as well as the specific mechanisms of action underlying this effect. We will focus on the alveolar process, the part of the jawbone that contains the tooth sockets. The unique ability of the alveolar process to remodel provides us with an excellent system for studying Ras signaling function in bone development.
Specific Aim 1 will characterize the alveolar process phenotype in CS patients and mouse model.
Specific Aim 2 will determine the cellular mechanisms that underlie Ras involvement in alveolar process formation. Finally, Specific Aim 3 will determine the mechanism by which Ras signaling regulates bone cell function, and also determine the feasibility of using small molecules to treat CS. To accomplish these goals we will examine patients' radiographs and analyze various mouse genetic models by morphological, histological, cellular, and molecular techniques. This project is significant because a better understanding of the mechanism by which Ras signaling disrupts bone development will enable us to move towards developing new and improved strategies for diagnosis and treatment of CS in particular and RASopathies in general.

Public Health Relevance

Proper formation of the alveolar process, the part of the jawbone that contains the tooth sockets, is a prerequisite for a healthy, functional head. In a group of medical genetic syndromes, this process is abnormal, leading to severe functional and cosmetic consequences. A better understanding of alveolar process formation can help us to devise new and improved diagnosis and treatment strategies in these syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE023702-03
Application #
8893784
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Tapaltsyan, Vagan; Eronen, Jussi T; Lawing, A Michelle et al. (2015) Continuously growing rodent molars result from a predictable quantitative evolutionary change over 50 million years. Cell Rep 11:673-80
Goodwin, Alice F; Tidyman, William E; Jheon, Andrew H et al. (2014) Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Hum Mol Genet 23:682-92