Project Overview
Rett syndrome (RTT) is a severe neurological disorder that primarily affects girls, occurring in about 1 in 10,000 births. Children with RTT experience developmental challenges, including difficulty with movement, communication, and repetitive behaviors. The condition is mainly caused by mutations in the MECP2 gene, which is essential for brain development and normal neuronal function.
Recent studies suggest that these genetic mutations may disrupt primary cilia—small, hair-like structures on the surface of cells that help neurons communicate. Our research has found that neurons with RTT mutations have fewer and shorter cilia, which may lead to problems in brain signaling, including abnormal calcium levels and excessive neuronal activity. However, the exact link between MECP2 mutations and ciliary dysfunction remains unclear.
In this study, we aim to fill this knowledge gap and explore whether restoring primary cilia can help correct neuronal dysfunction in RTT.
Aim 1: We will investigate how cilia defects differ in various types of brain cells by growing 3D minibrains (organoids) in the lab. We will also examine post-mortem brain tissues from RTT patients to confirm if these abnormalities are present in human brains.
Aim 2: Since cilia help regulate calcium levels in neurons, we will study whether their loss in RTT leads to excessive neuronal activity. We will test whether restoring cilia can bring calcium levels back to normal.
Aim 3: We will test Tubacin, a drug known to promote cilia growth, to see if it can restore cilia formation and improve neuronal function in RTT models. If successful, this could lead to new treatment strategies to improve the lives of individuals with RTT.
