Research Focus

Thesis Project Title: CREB3L1 Is Necessary For Bone Development As Evidenced By Mutations That Cause Osteogenesis Imperfecta

Collagen is a primary component of osseous tissue. The importance of collagen in healthy bone is exemplified by the disease osteogenesis imperfecta (OI), in which deficiency or abnormality of type I collagen results in bones that are brittle and predisposed to fractures. Exome sequencing of a family presenting with OI phenotypes ranging from mild with few fractures to prenatal lethal revealed a mutation in CREB3L1, a basic leucine zipper (bZIP) transcription factor. CREB3L1 has been reported once before in association with OI but the disease mechanism is unclear. Collagen proteins are quite large and their transport from the endoplasmic reticulum (ER) to the Golgi for packaging and eventual secretion is achieved using specialized secretory pathways. A closely related protein to CREB3L1, CREB3L2, has a role in regulating one such pathway in chondrocytes and is important for proper cartilage formation. Impaired functionality of CREB3L1 due to mutation may perturb this pathway in osteoblasts (bone-forming cells) and lead to reduced type I collagen in bone, explaining the OI. Fibroblasts from the proband are available but they do not express CREB3L1 at high levels. Therefore, using both induced pluripotent stem cell (iPSC)-derived osteoblasts made from our patient’s cells and zebrafish bearing the family mutation, we will model CREB3L1-associated OI, looking for evidence of impaired secretion and defining the secretory pathway in which CREB3L1 plays a role. Expression in a number of secretory cell types in which collagen is not a primary protein product, including pancreatic β-cells and goblet cells, suggests CREB3L1 may be involved in more generalized pathways as well.

Awards
Summa Cum Laude, 2011 (Gordon College)
Phi Alpha Chi Honors, 2011 (Gordon College)
Sigma Xi, 2011 (Gordon College)
Winner Best Poster Biological Sciences, Gordon College Undergraduate Research Symposium, 2010

Publications
Keller RB, Demellawy DE, Quaglia R, Finegold M, Kapur RP. Methylation Status of the Chromosome Arm 19q MicroRNA Cluster in Sporadic and Androgenetic-Biparental Mosaicism-Associated Hepatic Mesenchymal Hamartoma. Pediatr Dev Path 2015;18:218-227 PMID: 25751191.

Keller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, Hofmann I, Agarwal S. CTC1 mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 2012;59:311-314 PMID: 22532422.