Susan M. Mendrysa - US grants

PROJECT SUMMARY Therapeutic intervention for prenatally diagnosed craniofacial defects holds promise for improved quality of life. Early detection, however, requires an improved understanding of the genetic factors underlying the craniofacial dysmorphologies. We have recently identified a role for MDM2, a ubiquitin ligase that negatively regulates the p53 tumor suppressor protein, in craniofacial development. Mice hypomorphic for Mdm2 exhibit craniofacial defects including cleft palate that are strain-dependent, suggesting that these genetic backgrounds encode variation at modifier loci which affect craniofacial development and the severity of craniofacial anomalies. The overall goal of this project is to obtain detailed information about the head and face phenotype of Mdm2 hypomorphic mice, which will guide future mechanistic studies of craniofacial development and form the basis for unbiased, forward genetic approaches to identify novel modifiers of craniofacial malformation. In Specific Aim 1, we gain insight into the cells, tissues, and structures altered by low MDM2 expression by quantifying the craniofacial dysmorphologies in Mdm2 hypomorphic mice. In Specific Aim 2, we examine the gene regulatory networks underlying the penetrance and expressivity of craniofacial anomalies in Mdm2 hypomorphic mice by obtaining detailed information about the differences in gene expression in embryos on the sensitized and nonsensitized genetic backgrounds. Together, our studies contribute to the mission of the National Institute for Dental and Craniofacial Research (NIDCR) to develop new early detection and personalized therapeutic intervention strategies for craniofacial defects by yielding new understanding of the gene and protein networks that govern craniofacial development and by providing new insight into how perturbing these networks influences clinical severity.

PROJECT SUMMARY The creation of highly innovative solutions to complex problems impacting human health requires research teams that are rich in cognitive diversity. Cognitive diversity represents the bringing together of people with different backgrounds, viewpoints, and life experiences and is a hallmark of highly innovative teams. Cognitive diversity correlates with identity diversity; it is thus imperative that the translational biomedical sciences workforce includes strong representation of Ph.D. scientists from diverse backgrounds that may imbue new ideas and perspectives to maximize scientific innovation. Unfortunately, cognitive diversity in research teams is currently limited because individuals from specific racial and ethnic groups, those with disabilities, and individuals with low socioeconomic backgrounds, remain significantly underrepresented (UR) in the biomedical sciences. Here, we propose to develop, apply, and evaluate a Postbaccalaureate Research Education Program (PREP) that will help prepare recent college graduates from UR backgrounds to enter and successfully complete a Ph.D. or dual- doctoral degree program in translational biomedical sciences. At Purdue University, PREP Scholars will have the opportunity to enhance their skill set in four main areas: research aptitude; academics; professional development and career planning; and community and resiliency. Scholars will engage in a yearlong, mentored research experience with an emphasis on preclinical translational studies. The Purdue PREP curriculum is adaptive; Scholars will use an Individual Development Plan (IDP) as a framework and will participate in the educational, professional development, and career planning activities that prepare them for admission to high caliber graduate programs and are aligned with their future career goals. Scholars will be introduced to the breadth of biomedical research and research- related careers along the translational pipeline available to a Ph.D. scientist. The Purdue PREP will adopt a multi-layered, hierarchical approach to mentoring in which each Scholar will work with a network of faculty and near-peer mentors with complementary skills that will provide a broad range of expertise and psychosocial support to enhance Scholars' success. PREP faculty mentors and Scholars will undergo parallel cultural competency training focused on issues of diversity and inclusion as they relate to the academic research environment in order to improve cross-cultural communication and enhance UR student experience. Success will be measured by > 75% of Scholars entering a high quality Ph.D. or dual-doctoral (e.g. DVM-Ph.D.; MD-Ph.D.) degree program upon completion of the one-year Purdue PREP. Formative and summative evaluations will be used to assess Scholars' persistence and progression to a Ph.D. and also the impact of the PREP on fostering an institutional climate of diversity that may enhance UR retention.