This award will both fund research to identify genomic mutations that have made humans uniquely susceptible to certain craniofacial disorders, as well as provide training and career development for Dr. Lowe to apply his quantitative background to research focusing on human health and disease. Mice have long been the favored system for mammalian genetics and development. Mice and humans share many fundamental features of mammalian development, making it possible to model many aspects of human health and disease using the mouse system. However, there are anatomical and physiological specializations in both species. For example, humans have a different dental pattern than rodents. Even compared to other great apes, humans have reduced jaws and greatly enlarged cranial capacity. The very traits that underlie human biology may also increase susceptibility to particular diseases, such as craniosynostosis and skull abnormalities, dental impaction, malocclusions, and temporomandibular joint and muscle disorders. It is now possible to begin understanding the molecular basis of human specific traits and disease susceptibilities, by combining large scale surveys of human specific DNA changes, with functional data on regulatory elements, flanking genes, and phenotypic effects in model systems. Multiple research studies have reported links between the serotonin system and skull development in humans, a link that has not been seen in mice. Dr. Lowe presents preliminary data showing that humans have a transposon insertion that upregulates expression of the serotonin receptor HTR1B in developing sutures, a molecular change likely to contribute to both delayed suture closure and sensitivity to serotonin signaling during skull development. During the award Dr. Lowe will: (1) identify the cells and tissues affected by the human specific enhancer, (2) recreate the human specific regulatory change and identify the phenotypes that result from similar expression of HTR1B in sutures of mice, (3) expand beyond this example to test whether similar lineage specific regulatory changes have reshaped other unique features of human craniofacial development. The results from this work are expected to have a positive impact on translational medicine by making physicians aware of the molecular mechanisms linking the serotonin system and skull development, and possibly suggesting new strategies for promoting suture patency when synostosis is detected early. This work will be conducted in the Developmental Biology Department at Stanford University and mentored by Professor David Kingsley, an expert in vertebrate genetics and skeletal development with an outstanding track record of preparing trainees for independent careers. Stanford University has extensive research infrastructure to support the proposed research. Dr. Lowe will receive formal training in histology, craniofacial development, and the use of xray computed tomography to quantify bone morphology, volume, and density. He will attend multiple Stanford, Bay Area, and international meetings in skeletal and craniofacial development, to provide broad exposure to problems and approaches in the field. Dr. Lowe will also be mentored by experts in molecular biology, genetics, and developmental biology to augment his background in computer science and immerse him in research projects related to human health and disease. Extensive practice in both speaking and writing will accompany the planned experimental work. The combination of research and training activities will prepare Dr. Lowe to become an independent investigator, managing his own interdisciplinary research lab. Dr. Lowe's unique background will bring innovative new approaches to the field, and should lead to important new insights into both the genomic and genetic basis of human craniofacial traits and disease susceptibilities that are unique to humans.

Public Health Relevance

The proposed research and career development are relevant to public health because much of what is known about human craniofacial development has been transferred from model organisms, yet there are some unique aspects of human skull development that may make humans particularly susceptible to certain disorders. We can now identify particular genomic events that may underlie craniofacial traits and disease susceptibilities in humans. Our functional studies of these genomic differences will make it possible to build better models of human disease and to improve our understanding and treatment of human craniofacial disorders.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Mentored Quantitative Research Career Development Award (K25)
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NIDR Special Grants Review Committee (DSR)
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King, Lynn M
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Song, Janet H T; Lowe, Craig B; Kingsley, David M (2018) Characterization of a Human-Specific Tandem Repeat Associated with Bipolar Disorder and Schizophrenia. Am J Hum Genet 103:421-430
Lowe, Craig B; Sanchez-Luege, Nicelio; Howes, Timothy R et al. (2018) Detecting differential copy number variation between groups of samples. Genome Res 28:256-265