This is an application for an Independent Scientist Award (K02) to the National Institute on Aging (NIA). Dan Nicholson, Ph.D. is an Assistant Professor in his sixth year as a faculty member in the Department of Neurological Sciences at Rush University Medical Center. Throughout his career, Dr. Nicholson has established a strong record of publications, including in his recent years as an independent investigator. He has also been successful in obtaining peer-reviewed funding from both federal and non-federal sources. Since joining Rush in 2009, Dr. Nicholson has leveraged his research training and developed a powerful technique called proteomic recon- structive microscopy, with which he is examining age-related hippocampal dysfunction and Alzheimer's dis- ease (AD)-linked channelopathies. However, increasing administrative and teaching duties hamper Dr. Nichol- son's research progress and potential, such that he is able to devote only ~50% of his time on research into the proteomic/integrative degradation of hippocampal neurons in aging and AD. This K02 award would relieve Dr. Nicholson of some of these restrictions and allow his research career to enter the next phase via (1) tutorial training in computational neurobiology and constructing morphologically realistic computational models of neurons; (2) tutorial training in two-photon laser scanning microscopy Ca2+-imaging of hippocampal dendrites; (3) applying next-generation proteomic imaging methods to hippocampal neurons, thereby enabling him to build both morphologically and proteomically realistic computational models of hippocampal neurons from rodents and human AD cases and their non-demented matched controls; (4) enabling him and his laboratory to generate sufficient data for grant applications including a new R01 and a smaller grant to the NIA; (5) enabling him to spend more time mentoring and interacting with his two graduate students and three postdoctoral fellows; and (6) engaging collaborators from outside the field of hippocampal neurobiology to build proteomically and morphologically realistic computational models of neurons from other brain regions vulnerable to aging, neurodegenerative diseases, and psychiatric disorders. The resource stability and protected time resulting from this K02 award would ultimately support several new projects exploring the signaling networks comprising voltage- and calcium-signaling interactomes in neuronal dendrites, with a particular focus on how they change during chronological aging and AD pathogenesis. Thus, the proposed experiments in this K02 application have broad significance and will have a substantial impact on Dr. Nicholson's research career via (i) the provision of enhanced research skills and knowledge complementary to his extant expertise; (ii) identifying new potential drug targets to treat AD; (iii) being the first to construct morphologically and proteomically realistic computational models of hippocampal neurons in the human brain; and (iv) unveiling the interaction of ion channels that drive aberrant neuronal signaling in ADTg mice, which will steer interpretation of the functional consequences of AD-linked changes in the single-dendrite proteome in human neurons.