Identification of Novel Mechanisms in Alzheimer's Pathogenesis and Progression
Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people in the world, but there is no effective therapy. Understanding molecular events leading to AD is vital for the development of new treatments. Our goal is to study the role of death-associated protein kinase 1 (DAPK1) in AD using mouse models and to determine whether DAPK1 is important for neuronal cell death and the development of Alzheimer’s disease. This study could have a significant impact on our basic understanding of AD, and might eventually lead to AD.
Our goal is to study the role of death-associated protein kinase 1 (DAPK1) in Alzheimer’s disease (AD) using mouse models and to determine the relationship between DAPK1 and neuronal cell death in human AD.
Neuronal cell death plays an essential role in normal physiology for a biological process, however, when impaired or influenced by various factors, it may contribute to neurodegenerative disorders, including AD. Recent studies have shown that DAPK1 might have a critical role in AD. We recently discovered that DAPK1 expression is markedly increased in 75 percent of human AD patient brains. Moreover, we showed that DAPK1 regulates two major AD-related molecules: tau and amyloid precursor protein (APP). We have identified novel DAPK1 substrates that are involved in neuronal cell death and AD including N-myc downstream-regulated gene 2 (NDRG2). Thus, this proposal is designed to test our novel hypothesis that DAPK1 is a critical regulator in neuronal cell death and its deregulation, in the face of additional stresses, might contribute to the development of AD. We will first examine whether DAPK1 regulates neuronal cell death by affecting potential DAPK1 substrates and determine the novel molecular pathway by which DAPK1 regulates neuronal cell death. Next, we will examine neuronal cell death in vivo using novel animal models to determine the relationship between DAPK1 and neuronal loss. This study would provide novel insights into the critical mechanisms of DAPK1 in neuronal cell death and the development of AD, and provide a novel therapeutic option for AD treatments.
About the Researcher
Tae Ho Lee is an assistant professor in the Division of Gerontology, Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center. He received his PhD in the Department of Biochemistry at the McGill University in Montreal, Canada. He conducted his post-doctoral research in the laboratory of Dr. Kun Ping Lu at Harvard Medical School. He studied the role of protein post-translational modifications in aging and age-related diseases, including AD and cancer. His laboratory uses neuron-derived stem cells and mouse models to study the complex mechanisms involved in AD. The main goals of his research are to determine the molecular mechanisms by which post-translational modifications regulate AD, and to identify potential targets for drugs to cure or prevent disease progression. He is also actively involved in teaching and training research and clinical fellows.
My career goals have always been to develop an independent research science program, with an emphasis on Alzheimer’s disease (AD). I am drawn to the field of AD research by my fundamental interest in cellular signaling pathways, and in translating this advancing into effective treatments. This grant will allow me to test my novel hypotheses about the development of AD and provide me with the opportunity to become a successful independent investigator. Moreover, this award will provide an excellent opportunity to collaborate with clinicians in exploring the expanded therapeutic potential of novel DAPK1 targets discovered in my research. This award will also undoubtedly be a crucial step to acquiring further funding for my research program, thereby maximizing my potential to integrate the highest level of research with various professional activities to achieve my goals. It is hoped that in 20 years, with my tenacity and perseverance, my research and that of other team efforts will lead to the cure of AD.
First published on: July 26, 2017
Last modified on: April 6, 2020