Supply and Demand of Proteins During Neuronal Growth and Extension

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0932590ShahINTELLECTUAL MERITThis project addresses the fundamental relationship between the production, delivery, and demand of neuronal proteins during axonal growth. The global hypothesis to be tested is that axonal transport and local protein production are primary suppliers for the resources needed for neuronal growth, and are regulated in part by the local mechanical environment of the neuron. This hypothesis will be addressed by using a multidisciplinary approach involving molecular and cellular biology, high-resolution imaging and image processing, and cell biomechanics.Any number of candidate proteins may be selected to study neuronal supply and demand. However, the specific cargoes to be considered in this project are those essential for growth, transport, and protein synthesis: mitochondria, responsible for fulfilling ATP-dependent energetic requirements for the neuron, vacuoles, responsible for supplying plasma membrane required for expansion of neuronal surface area; ribosomes, responsible for protein synthesis; and mRNA, which provides the template transcript for protein synthesis.Several aspects of the proposed research are transformative, including the development of novel engineering approaches to examine and quantify neurobiological processes, and the use of a systems approach to understand the subcellular function of neurons. In the long term, this basic science project has implications for providing a basis for the progression of neurodegenerative diseases linked to defects in axonal transport, such as Alzheimer's and Lou Gehrig's Disease (ALS). Additionally, this bioengineering approach to understanding physiological processes within the neuron will facilitate a valuable data-driven approach to modeling and manipulating the dynamics of neuronal cargo supply and demand, and the allocation of cellular resources. Finally, given the ubiquity of transport processes in cellular systems, it is expected that general principles identified from this project will be relevant to the function and dysfunction of non-neuronal cells. BROADER IMPACTS In addition to the biomedical and basic scientific impacts highlighted above, the proposed plan also impacts education, research training, and community outreach. In the classroom, research results will be integrated into two bioengineering courses based on cell physiology, both of which draw heavily on current research approaches for their course material. Given the multi-disciplinary nature of the proposed research, training opportunities for undergraduate and graduate students from backgrounds in both engineering and biological sciences will be provided. Thus far, students from multiple backgrounds have successfully been recruited to the laboratory of the PI, and the continuation of this success is anticipated based on the emphasis on an open, collaborative work environment. This cross-disciplinary, team-based approach is critical for training a new generation of biomedical scientists and bioengineers. Additionally, participation in a variety of outreach programs will be initiated or continued. A new Neuro-Bioengineering Research Program (NBRP) will be created, in conjunction with the QUEST program at Eleanor Roosevelt High School, whose enrollment consists of student populations under-represented in science and engineering. Implementation has already been started for portions of this program, which exposes middle and high school students to career options in bioengineering, introduces them to research methodology and scientific writing, and provides them with access to state-of-the-art laboratory facilities. Active participation in the Molecular and Cellular Bioengineering Research Experiences for Undergraduates (REU) Program will also be continued. It is a priority to admit students to this program who have limited access to research opportunities at their home institutions. The vision of the PI is consistent with that of the Fischell Department of Bioengineering, the Clark School of Engineering, and the University of Maryland; ultimately, the aim is to encourage and facilitate the participation of K-12, undergraduate, and graduate students in multidisciplinary biomedical research, in an effort to attract the finest students to this exciting field.