State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Disruptions of hindbrain development are implicated in multiple human disorders that cause significant morbidity and mortality such as Chiari malformations, sudden infant death syndrome and autism. The Mathl gene encodes a basic helix-loop-helix transcription factor whose function is necessaryfor the creation of multiple neuronal subtypes in the developing hindbrain, including those involved in breathing control. My proposal seeks to understand how Mathl contributes to normal hindbrain development in an effort to better understand derangements that cause serious neurodevelopmental human conditions. My goal is to determine how spatial and temporal cues specify the cellular fates of MafM-lineal cells derived from the rhombic lip.
The specific aims of the project are to 1) disrupt Math1function in a spatially- restricted manner to define the sites of origin of various rhombic lip derivatives;2) determine the time of origin of Ma#77-lineal cells;and 3) selectively eliminate Mathl-dependent cell populations based on time of origin. I will use conditional knockout systemsto test the hypothesis that disruption of Mathl in a spatial- or time-dependent manner causes deletion of specific subsets of neurons, resulting in different phenotypes depending on the cell groups that are affected. This strategy will allow me to construct a spatial and temporal fate map of the murine rhombic lip, pinpoint neurons essential for breathing control, and evaluate physiological and behavioral consequences resulting from loss of specific neuronal subsets in the hindbrain. My overall career goal is to become an independent physician/scientist who focuses on understanding congenital neurological abnormalities. I will spend the majority of my time running a basic research laboratory, but I will also see a select group of patients with brain malformations. My ultimate goal is to characterize and identify genes that are responsible for these abnormalities in the hopes of better understanding what causes them and how they may be effectively prevented or treated, if possible. Baylor College of Medicine provides the perfect environment for my success. My mentor, Dr. Huda Zoghbi, is an internationally known physician/scientist with a tremendous training record. Departmental support of my research career, interaction with a Scientific Advisory Committee, and formal coursework at Baylor and elsewhere will also help me to achieve my goals. PERFORMANCE
