Alzheimer's Disease affects 5.4 million Americans [1] and by 2030, approximately 13.8 million people 65 or older are projected to have the disease [2]. Even more individuals will experience normal age-related cognitive decline, mild cognitive impairment, and impairments in long-term memory formation. It is therefore critical to understand the mechanisms underlying memory formation in the context of normal age-dependent cognitive decline. This proposal tests whether Per1 is a key novel mechanism that links aberrant epigenetic transcriptional repression in the aging brain with age-related impairments in both circadian rhythmicity and long-term memory formation. First, this proposal will test whether the repressive activity of histone deacetylase 3 (HDAC3) contributes to age-related impairments in both memory formation and gene expression. Next, it will determine whether Per1 is a mechanism through which HDAC3 limits memory formation in the aging brain. Finally, using a CRISPR/dCas9-based genetic engineering approach, this project will test whether site-specific epigenetic manipulations at Per1 can ameliorate age-related impairments in memory formation. Together, the experiments in this proposal will determine whether epigenetic dysregulation of the circadian gene Per1 in the dorsal hippocampus contributes to age-related impairments in long-term memory formation. The proposed project will also help the candidate, Dr. Janine Kwapis, achieve her career goal of becoming an independent investigator at a research-focused institution. This project provides training in cutting-edge research skills, including the development and application of CRISPR/dCas9 technology and training in circadian rhythm research. Further, the proposed studies will lay the foundation for a research program that extends well beyond the proposed grant. The University of California, Irvine provides an ideal environment for training the candidate in these new technical skills, with world-renowned experts in memory, aging, circadian rhythms, and molecular biology. Further, UCI provides an intellectual environment that encourages collaboration and cooperation, allowing the candidate to grow as a scientist and prepare for a successful career. In addition to the proposed research, Dr. Kwapis will engage in a number of activities designed to prepare her to successfully achieve independence, including training in grantsmanship, presentations, scientific writing, didactic training, job application, and lab management. The systematic plan proposed here (including both the research plan and the candidate development plan) is calibrated to produce a successful, independent research scientist who performs unique cutting-edge research that can support a new laboratory and is well-positioned to receive future R01 funding.
Alzheimer's disease is projected to affect 13.8 million people 65 or older by 2030 and even more individuals will experience normal age-related cognitive decline, mild cognitive impairment, and dysfunctional memory formation. Understanding the neural mechanisms underlying these age-dependent impairments in memory is critical to developing new treatment strategies to prolong healthy cognitive function as the population ages. This proposal will examine the epigenetic regulation of a key circadian rhythm mechanism that may be pivotally involved in normal age-related cognitive decline and has the potential to unlock novel therapeutic avenues.
