This is a Competitive Revision Application to grant 2 R01 NS045217-06 titled "Molecular components of A-type K+ channels" in response to Notice Number (NOT-OD-09-058) titled: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Project NS045217 is focused on the study of fast transient A-type K+ currents (IA), currents that are essential for the proper functioning of the brain and the heart. The project seeks to establish the molecular composition of the ion channels responsible for the generation of these currents in mammalian neurons. Work supported by this grant led to the discovery of a novel family of proteins that associate with IA channels known as DPPLs, of which two members are currently known DPP6 (or DPPX) and DPP10. The goal of the parent grant is to elucidate the functional significance of DPPL proteins. The grant is focused on CA1 hippocampal pyramidal cells, neurons that are important in spatial learning and in the pathogenesis of epilepsy, and prominently express one Kv4 protein Kv4.2 and one DPPL, DPP6. The experiments in the parent grant will test the hypothesis that DPP6 is an important component of Kv4 channels in CA1 neurons, determining the proper distribution, biophysical properties and dynamic modulation of the channels. Recent genetic studies have found association between DPPLs and human disease. Of particular significance is the observation, replicated in four independent studies, showing association between DPP6 and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, a fatal neurodegenerative disease characterized by motor neuron death. This competitive revision takes advantage of funds provided under the American Recovery and Reinvestment Act of 2009 to significantly expand the scope of the parent grant in order to investigate the relationship between DPP6 and ALS. The experiments are designed to answer key questions about the biology of DPP6 in motor neurons, which are critical to validate the association between DPP6 and ALS. The proposed supplement will contribute to the objectives of the Recovery Act, accelerating the tempo of research on the mechanisms of motor neuron disease and stimulating the economy by enabling the hiring of qualified additional staff and procuring additional equipment. The proposed research will also benefit the U.S. economy by contributing significantly to the understanding and eventual treatment of ALS, a devastating chronic and extremely debilitating disease that afflicts and kills thousands of people in the U.S. yearly and costs billions of dollars in health care costs. PUBLIC HEALTH RELEVANCE: This supplement will investigate the link between a protein known as a DPP6 and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). The proposed experiments seek to validate genetic evidence suggesting that variation in DPP6 predisposes to ALS. The study will advance our knowledge on the mechanisms of this devastating disease.
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