Intellectual merit. Actin-binding proteins are important modulators of cellular function. They are particularly important in the nervous system, where they modulate the function of the actin cytoskeleton, which in turn, modulates processes such as the formation of axons, dendrites and synapses; vesicle recycling, synaptic activity and synaptic plasticity. This project will determine the function of the recently discovered neuronal actin-binding protein Kelch-like 1 (or KLHL1). In particular, this research will expand our knowledge of the role that this novel structural protein plays in calcium channel function, which is critical for intracellular communication and neurotransmission. KLHL1 modulates calcium channel function by a newly identified pathway. This project seeks to establish the cellular mechanism of this novel type of modulation. The specific goals of this project are two-fold: (1) To determine the physiological impact of the elimination of KLHL1. The hypothesis is that the absence of KLHL1 in neurons results in altered neuronal function. (2) To determine the cellular mechanism by which KLHL1 modulates calcium channel function. The hypothesis is that KLHL1 interacts with the actin cytoskeleton within the neurons, altering the rate of endosomal recycling and resulting in the increased presence of calcium channels at the neuronal cell membrane.
Broader impacts. This research will contribute to the understanding of the function of key proteins involved in neurotransmission and the modulation of the electrical activity of the brain. The educational component of this project is to recruit under-represented minority undergraduate students to introduce science as a possible career, and to involve them in hypothesis-driven, high-caliber basic scientific research. Activities will be conducted to encourage participation of junior undergraduate minority students in research and careers in science and will include outreach science seminars. In parallel, students will be actively involved in full-time, hands-on laboratory work, seminar participation and data presentation. This will enable them to learn new techniques, to develop scientific ideas, to think critically, and to experience the thrill of science.
Intellectual Merit Our research helped our understanding of the function of key proteins involved in neurotransmission and the modulation of the electrical activity of the brain. Actin binding proteins are important modulators of cellular function; they are particularly important in the nervous system, where they modulate the function of the actin cytoskeleton, which in turn, modulates processes such as the formation of axons, dendrites and synapses; vesicle recycling, synaptic activity and synaptic plasticity. The intellectual merit of this project was its aim to determine the novel function of the neuronal actin-binding protein Kelch-like 1 (or KLHL1) as a modulator of excitability. The goal was to expand our knowledge of the function that this novel structural protein plays in calcium channel function, which is critical for intracellular communication and neurotransmission. In addition, this project was designed to characterize the modulation mechanism of excitability by KLHL1 via the newly identified pathway. The outcomes of this project accomplished the specific goals originally proposed: 1) We determined that of KLHL1 is an important physiological modulator of calcium currents, and that its absence not only alters neuronal calcium channel composition, but it affects neuronal activity and excitability: 2) We determined that long-term elimination of KLHL1 resulted in compensatory changes that balanced calcium currents, however this compensation did not rescue the synaptic deficits. 3) We corroborated by microscopy studies that KLHL1 is a modulator of calcium channel function KLHL1 through actions via the cellular organelle recycling endosome. Broader Impacts The broader impacts of this project were primarily to inspire and recruit under-represented and all other students into considering the possibility of future careers in science; and to expose students interested in science to all aspects of hypothesis-driven, hands-on scientific research in the laboratory and to showcase the thrill of discovery in basic science research. This project supported the training and participation of six URM students and a total of nine students from high school to post-doctoral levels. All students were actively involved in full-time, hands-on laboratory work, seminar attendance and data presentation. They learned new techniques, learned to develop scientific ideas and critical thinking, and in some cases, presented their research at national and local meeting, helping communicate science to the public. Other activities to encourage participation of junior undergraduate minority students in research and in careers in science were organized.
