Zhu Pilot Project Summary
Alzheimer's disease (AD), the leading cause of dementia worldwide, presents a substantial challenge in understanding, evaluating, and treating cognitive dysfunction—a core symptom of the disease. The failure of nearly all AD drugs that showed promise in animal models during clinical trials (99.6% failure rate) underscores a critical shortfall: inability to fully recapitulate complex molecular and cellular interactions in human AD. Our long-term goal is to reveal pathways of cognitive impairment in AD by decoding molecular dynamics of gene expression, revolutionizing research and drug development for mitigating AD cognitive decline. Our overall objective in this application is to determine cognitive decline during AD in a tissue-engineered brain-on-chip model integrated with a molecular nanobiosensor to monitor real-time cognition-associated gene expression. The rationale is that investigating cognition-associated gene dynamics can reveal novel biomarkers of AD-related cognitive dysfunction, and monitoring these genes in a brain-on-chip model constructed with human induced pluripotent stem cells (iPSCs) can lead to a reliable platform for assessing cognitive decline.
The overall objective will be achieved by pursuing two specific aims: (1) to design a nanobiosensor for monitoring AD-related cognition-associated gene expression in live cells; and (2) to monitor dynamic expression of these genes in a brain-on-chip AD model. For the first aim, a nanobiosensor will be designed to detect mRNAs of cognition-associated genes in live cells. The dynamic expression of these mRNAs will be monitored with this nanobiosensor during induction and reversal of AD. Under the second aim, a tissue-engineered brain-on-chip model with human iPSCs-derived cells will be constructed. Real-time gene expression of these mRNAs will be monitored in this model during AD. The proposed project is innovative because a novel nanobiosensor will detect spatiotemporal dynamics of cognition-associated gene expression, and this sensor will be integrated in a novel brain-on-chip AD model to assess cognitive dysfunction and recovery. This proposal is significant because it revolutionizes research and drug development for AD cognitive impairment by designing a reliable and high-throughput platform for assessing cognitive decline. This approach promises to bridge current research gaps by providing a more accurate, high-throughput method to assess cognitive dysfunction and therapeutic efficacy, thereby accelerating the development of effective AD treatments.