Lisa A. Schimmenti, M.D. - US grants

DESCRIPTION (provided by applicant): Ten percent of congenital blindness results from microphthamia, anophthalmia and coloboma. The genetic basis for most forms of microphthalmia, anophthalmia and coloboma remain unknown but it is hypothesized that the initial pathologic processes result from faulty embryonic development of the optic vesicle and optic cup. A critical event in eye development is closure of the optic fissure on the ventral surface of the optic cup. It has been observed that seventy percent of patients with microphthalmia, anophthalmia and coloboma have evidence of defective optic fissure closure. The overarching goal of this proposal is to identify transcripts that participate in the process of optic fissure closure. Through a thorough understanding of the list of transcriptional regulators controlling optic fissure closure, we can determine the underlying basis of optic fissure closure defects. In mouse and zebrafish models, Pax2 expression supports optic fissure closure while loss of Pax2 expression results in optic fissure closure failure. Using total RNA transcripts from both Pax2 expressing and Pax2 null embryonic optic cup and stalk containing tissue, a group of 66 differentially expressed transcripts were identified by microarray analysis. We propose to validate these transcripts to develop a list of Pax2 Eye Regulated Transcripts (PERTs) (Aim 1). Individual PERT function will be assessed in a zebrafish based forward genetic screen using anti-sense technology to identify optic fissure closure defective phenotypes (Aim 2). We will determine the capacity for each individual PERT to rescue the pax2a optic fissure closure defect in zebrafish (Aim 3). These studies would result in a greater understanding of optic fissure closure and provide a resource for the zebrafish community to study optic fissure closure with the ultimate programmatic goal of identifying the genetic basis of microphthalmia, anophthalmia and coloboma. PUBLIC HEALTH RELEVANCE Microphthamia (small eye), anophthalmia (nearly absent eye) and coloboma (cleft eye) are significant birth defects causing ten percent of childhood blindness. It is estimated that two in every ten thousand babies are born with microphthalmia, anophthamia or coloboma. For most families impacted by this group of birth defects, a causative genetic explanation remains unavailable. We propose to use zebrafish as a model organism to help discover the genes responsible for microphthalmia, anophthalmia and coloboma and to provide the zebrafish model as a resource to the research community to allow greater understanding of this group of birth defects.

PROJECT SUMMARY Physician scientists (MD-PhDs) are uniquely positioned to address many of the challenges at the forefront of modern medicine. During the first 14 years of support, the Mayo Clinic MSTP has dedicated itself to training talented and passionate students to be critical, productive physician scientists. Our mission is to prepare our students for academic careers in basic, translational and clinical research, focused on studying fundamental questions and translating basic discoveries into medical advances. The program philosophy is that the skills required for this type of academic career are best developed in a basic research setting. However, the unique quality of the physician scientist is the ability to integrate basic studies with translational and clinical research to ultimately advance the practice of medicine, and the Mayo Clinic MSTP strives continually to improve the integration of clinical and basic research training. First awarded an MSTP grant in 2003 and renewed twice, our MSTP has continued to develop and mature while maintaining aspects that were previously praised by reviewers. The main strengths of our MSTP are: ? An enthusiastic training faculty of 71 mentors who provide extensive opportunities for cutting-edge interdisciplinary training in basic, translational, and clinical research; ? Outstanding current trainees who are passionate about the study of fundamental biological processes of relevance to human disease; ? A highly competitive applicant pool; ? An autonomous admissions process that enables selection of students based on their prior research experiences and excitement for biomedical research; ? An effective recruitment and retention plan to enhance diversity, with three URM students who completed training during the past five years and 12 URM or students with disabilities currently in training; ? Integration of medical and graduate school curricula, which allows students to complete three required graduate courses and two laboratory rotations during MS1 and MS2; ? Programmatic features, including the MSTP Selectives, Weekly MSTP Conferences, MSTP Annual Retreat, MSTP Clinical Experiences Program and MSTP Clinical Re-Entry Course, as well as individualized development support that respond to specific needs of MD-PhD trainees; ? Strong institutional support for education, which enables us to fund our MD-PhD students throughout their medical and graduate training, providing exceptional flexibility in choosing thesis laboratories; ? Exceptional research resources that enhance our students' educational experiences; ? A dedicated, interactive, and supportive team consisting of the Director, Associate Directors, administrators and student leadership.