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RS1-00462-1: MicroRNAs in Human Stem Cell Differentiation and Mental Disorders

Public Abstract (provided by applicant)

during brain development in early life. For instance, by 2 years of age, autistic children have larger brains than normal kids, likely due to, at least in part, excess production of neurons and support cells, the building blocks of the nervous system. In autistic brains, how neurons grow various thread-like processes also shows some abnormalities. The cause of autism is complex and likely involves many genetic factors. These developmental defects are also associated with mental disorders caused by single-gene mutations, such as Rett syndrome and fragile X syndrome, the most common form of inherited mental retardation, whose clinical features overlap with autism. However, what causes the developmental defects in brains of children with different mental disorders is largely unknown.

In recent years, an exciting new regulatory pathway was discovered that may well contribute to the etiology of mental disorders. The major player in this novel pathway is a class of tiny molecules 21–22 nucleotides long, called microRNAs. Through a unique mechanism, these small molecules control gene expression during the development of many organs, including the brain through a unique mechanism. Their importance in mental disorders is underscored by the discovery that they are somehow associated with FMR1, the gene that is mutated in fragile X syndrome.

In this application, we will study the roles of microRNAs in human embryonic stem cell maintenance and differentiation into neurons. The activities of some microRNAs will be manipulated in stem cells or differentiated neurons and their effects will be accessed. These studies will help us further understand the biology of human embryonic stem cells, and how they cells can be controlled to differentiate into desirable neuronal cells once implanted into human central nervous system. Those fundamental knowledges are essential for the future development of stem cell therapies for a wide range of mental disorders and age-dependent neurodegenerative diseases.

Statement of Benefit to California (provided by applicant)

California is the most populated state in the US and has a large number of patients suffering from various mental disorders. The proposed studies in this grant application will contribute to the mission of developing novel avenues through stem cell research for the diagnosis, prevention and treatment of mental disorders.