The Influence and Regulation of Neuronal ROCK Signaling by IGF-1

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 DESCRIPTION (provided by applicant): The long-term career goal of Dr. Ashpole is to establish herself as a successful and well-funded, independent investigator in the field of aging, and in particular, the area of neuroscience. Thus far in her training career, Dr. Ashpole has been highly-productive with 12 peer-reviewed publications. Her doctoral training, in which she studied intracellular signaling cascades in neurons, laid a strong foundation for her current post-doctoral position. For this, Dr. Ashpole joined the laboratory of Dr. William Sonntag to study the mechanisms underlying IGF-1-dependent changes in learning and memory. Dr. Sonntag is a leading authority in the field of neuroendocrine signaling and aging. Dr. Sonntag's laboratory offers a variety of in vivo approaches which will expand her technique repertoire and allow her to become a well-rounded research scientist. The research strategy outlined in this proposal incorporates the in vitro techniques used to study signaling cascades from her doctoral training with the in vivo techniques in the Sonntag laboratory. The training program includes a mixture of laboratory training and mentoring interactions with Dr. Sonntag and an advisory council. Together, this program will ensure the Dr. Ashpole transitions to an independent investigator in the field of aging. The age-dependent loss of IGF-1 has been shown to contribute to cognitive impairment; however, the pathophysiological mechanisms underlying this effect remain to be established. The proposed studies will address this gap in knowledge by examining potential signaling pathways that may induce changes in neuronal structure and function when IGF-1 is reduced. Our preliminary data indicates that IGF-1 inhibition leads to the upregulation of the Rho-associated protein kinase (ROCK). Dr. Ashpole hypothesizes that this IGF-1- dependent upregulation of ROCK contributes to age-related impairments in learning and memory, as RhoA/ROCK activity is known to negatively influence neuronal structure and function. To better understand how IGF-1-regulated ROCK contributes to age-related cognitive decline, Dr. Ashpole will first examine the mechanisms by which IGF-1 regulates ROCK activity in Specific Aim 1. In Specific Aim 2, Dr. Ashpole will examine the effects of IGF-1-regulated ROCK on neuronal structure. Finally, in Specific Aim 3, Dr. Ashpole will examine how IGF-1-regulated ROCK influences neuronal function by measuring long-term potentiation as well as learning and memory within our mouse models. While growth hormones are often recognized solely for their contribution to cell development, it is obvious that IGF-1 plays an important role in maintaining neuronal function throughout our lifetime. Thus, this proposal addresses an area of research that is of high relevance in the field of aging. The studies that have been proposed will explore novel pathways that contribute to cognitive impairment when IGF-1 is reduced in advanced aging. Because of this, findings from this project may have long-term implications in improving the quality of life in the aging population.