Grants We Funded

Abstract
Cleft lip with or without Cleft Palate (CL/P), the most common congenital craniofacial anomaly in humans, occurs approximately in 1 in 500-700 live births worldwide and results in disfigured facial appearance, impaired feeding, and defective speech. Currently, there are few reliable genetically engineering animal models for CL/P. Our goal is to use our compound Pbx mutant mice with fully penetrant CL/P as a genetic model for correction of CL/P. Our data demonstrates that Pbx requirement for proper midfacial morphogenesis is mediated by genetic control of canonical Wnt signaling in the midface epithelium. Impaired Pbx function in cephalic epithelium is sufficient to cause loss of Wnt signaling, resulting in perturbed apoptosis and abnormal morphogenesis of the upper lip. Pbx-Wnt signaling cascade at the embryonic lambdoidal junction has been shown to mediate midfacial morphogenesis via localized apoptotic programs. Previously, we not only developed a unique compound Pbx-deficient murine model with fully penetrant CLP, but also demonstrated genetic rescue strategies to reconstitute Wnt signaling and correct midface clefting. In view of these findings, our hypothesis is that mammalian midface morphogenesis requires tight genetic control of apoptotic programs regulated by a Pbx-Wnt cascade at the embryonic lambdoidal junction (lambda; the seam where lateral and medial frontonasal processes fuse with the maxillary process). To test our hypothesis we will assess whether repair of CL/P can be obtained in our mouse model by prenatal microsurgical intervention, through restoration of Wnt-controlled craniofacial developmental programs via implanted collagen microspheres at the midface lambda junction. We seek to mimic the uterine environment by using a novel whole-embryo culture method to grow mouse embryos for 48 hours in culture, after surgical implantation of Wnt-soaked collagen microspheres ex utero at the embryo's midface lambda junction. By this approach, we plan to open novel avenues towards prenatal repair of this mutilating facial abnormality.

Biography
Dr. Jason Spector is a nationally recognized clinician, researcher and educator. He holds two patents, and has been an integral part several Cornell University-Weill Cornell Medical College translational research teams. He participates in the NIH and Howard Hughes Medical Institute sponsored Clinical Summer Immersion for Biomedical Engineering Program, mentoring engineering doctoral students. Since 2007, he has been a lecturer at Cornell University's Biomedical Engineering Science and Technology course, "Approaches to Problems in Human Needs." Dr. Spector serves as an Ad-Hoc reviewer for six prestigious medical journals, and has presented at national and international medical meetings. He recently served as Moderator of the Emerging Technologies Section, at the American Surgical Congress in 2011.