Testing the potential of peptides as a treatment for autism

This study aims to investigate the efficacy of PEDF peptides as a medication for autism spectrum disorder and ADNP syndrome. 

Pigment Epithelium-Derived Factor (PEDF) is localized at chromosome 17p13.3, and deletions or duplications of this chromosome region result in neurodevelopmental disorders, such as Miller-Dieker syndrome and 17p13.3 duplication syndrome, related to ASD. We recently have found that PEDF plays a critical role in neuronal morphogenesis and neural activity in vivo, including neurite formation, spine formation and calcium signaling. Studies have indicated the possibility of PEDF-derived peptide as a potential medication for tumors and retinopathy. However, little is known about PEDF functions in neurodevelopment in the cortex and the effects of the peptides in neurodevelopmental disorders, such as autism. 

In addition, we are interested in testing the peptides in the ADNP syndrome, which is caused by a mutation in the ADNP (activity-dependent neuroprotective protein) gene and associated with a variety of symptoms, such as ASD, ADHD and intellectual disability. 

Autism spectrum disorder (ASD) is characterized by four core symptoms, which are 1) impaired communication and social interaction, 2) restrictive interests, 3) repetitive behaviors, and 4) irritability. Many patients with autism spectrum disorder experience daily pain and frustration, as many cannot make friends, engage in social activities, or find comfort in most environments. ASD is a huge burden on not only patients but also their families and local and federal health systems. There is an urgent need to alleviate these burdens, but to date, no effective treatments addressing the cause of autism spectrum disorder exist. Current medications are limited only to reducing irritability. To relieve the severe burdens of this disease, developing improved and novel medications that can address the other core symptoms of ASD are essential. 

Etiology of the 17p13.3 Microdeletion (Miller-Dieker Syndrome) and Microduplication Syndrome Related to Autism 

The aim of this project is to study the etiology of the 17p13.3 microdeletion (Miller-Dieker syndrome) and microduplication syndrome. We are interested in determining the functions of 26 genes involved in the 17p13.3 microdeletion (Miller-Dieker syndrome) and microduplication syndrome associated with autism.

In chromosome 17p13.3, there is a hotspot, called MDS critical region, which is often deleted or duplicated in MDS and the 17p13.3 duplication syndrome. there are 26 genes in MDS critical region, but the functions of many of those 26 genes in cortical development have not been clarified. Therefore, to understand the etiology of neurodevelopmental disorders, it is of importance to investigate the functions in neurodevelopment.

It is known that Lis1, Crk and 14-3-3epsilon in 17p13.3 are responsible genes for MDS. However, the MDS critical chromosome region contains 26 genes, including PEDF (Serpinf1). Thus, we know a bit about MDS etiology, but we still don't know many things about MDS. 

Neuronal Morphogenesis in the Developing Cortex

This project aims to investigate the cellular and molecular mechanisms underlying neuronal morphogenesis, such as neurite formation, spine formation, and synaptogenesis, in the developing cerebral cortex.

Neuronal morphogenesis occurs relatively in early-stage of cortical development. The defects in these early steps largely affect the later steps, such as neural connection and activity.  Recent studies using ASD animal models indicate the defects in neuronal morphogenesis, not only spine/synapse formation but also neurite formation. Thus, a more comprehensive understanding of neuronal morphogenesis is essential to understand the etiology of neurodevelopmental disorders.

Neurite formation is an early cellular event during cortical developments. The defects in this step affect many later steps, such as neural connectivity and activity. Therefore, the full understanding of the mechanisms underlying neuronal morphogenesis is essential for advancing our knowledge about neurodevelopmental disorders, such as autism spectrum disorder.

14-3-3 Functions in the Brain  

The aim of this project is to clarify the functions of 14-3-3 proteins, especially 14-3-3epsilon, in the brain. We are interested in the 14-3-3's roles in neuromorphogenesis, neural connectivity, neural activity, and neurobehavior.

14-3-3 is a multifunctional protein in multiple cellular events, such as cell proliferation, cancer, and apoptosis. We have worked on the 14-3-3 functions in brain development. 14-3-3 regulates multiple cellular steps during cortical development from neurogenesis to neural activity.

We have worked on 14-3-3 functions in cortical development for a long time, but 14-3-3 is a mysterious protein, not only its name but also its functions. We still don't know a lot about 14-3-3.

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