Thursday, November 21, 2024
11/21/2024
Project Summary Alzheimer's disease and related dementia (AD/ADRD) affect a large percentage of population in the US creating a signficant health care burnden to society. A few environmental stressors have been identified as risk factors for ADRD, including lead (Pb). Exposure to these chemicals particularly during vulnerable developmental periods can result in adverse neurological outcomes later in life, including ADRD. However, less is known about the genetic risk factors that act as confounding factors with Pb contributing to ADRD onset. Furthermore, Pb exposure can affect aging hallmarks, while aging is a well-established risk factor for ADRD. Hence, it is crucial to understand how developmental Pb exposure interacts with aging hallmarks, ultimately influencing the biological “age” of the CNS and its repercussions. The goal of the proposed work is to identify and validate Pb- interacting genetic risk factors contributing to the etiology of ADRD in “age”-matched human neuronal models. Our preliminary studies verified the presence of ADRD pathogenic marks in 2D neuronal culture with developmental Pb exposure; and demonstrated the feasibility of using human mouse chimeric brain to provide the proper extracellular environment for neuron aging. Novel engineering platform to enable neuronal sorting based on the formation of tau aggregation; and track changes in age-related epigenetic features were also demonstrated which collectively form a strong technical foundation for our two research aims. In SA1, we will idenitfy genetic risk factors coupled with developmental Pb exposure that contribute to ADRD etiology. To do that, we will establish and validate reporter plamsids for ADRD pathogensis; screen for genentic risk factors in 2D culture models for Pb-coupling genetic risk factors; and validate select genetic targets in human neuronal models (2D/chimera). In SA2, we will characterize changes in aging hallmakers after Pb exposure and recaptiulate “aging” features in 2D culture. To do that, we will characterize the effects of Pb exposure on the installation of aging hallmarks in human mouse chimeric model and 2D culture focusing on nucleus, mitochondrion and mitochodnrial-nuclear signaling. The collective knowledge will guide the design of an “age” accelerating mixture that can facilitate neuronal maturation and degeneration in 2D cultures. Upon completion, we will develop an enabling platform for identification of GxE interactions intricated by developmental Pb exposure in aging brains; and verify our central hypothesis that Pb influences the development of ADRD by intertwining its effects with other genetic risk factors and the aging process.
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