FEN-BIAO GAO, PhD

		Establishment of Frontotermporal Dementia Patient-Specific Induced Pluripotent Stem (iPS) Cell Lines with Defined Genetic Mutations We propose to generate induced pluripotent stem (iPS) cells from skin cells derived from human subjects with frontotemporal dementia (FTD). FTD accounts for 15ó20% of all dementia cases and, with newly identified genetic causes, is now recognized as the most common dementia in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal and temporal lobes and other brain regions, resulting in behavioral changes and memory and motor neuron deficits. The median age of onset for this devastating disease is 58 years, and disease progression is rapid, with death in 3ó8 years.
Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD remain poorly understood. Genetic causes are estimated to account for ~40% of FTD. In addition to tau identified in 1998, mutations in three causative genes have been identified during the last three years. The identification of FTD mutations opens exciting new avenues for understanding the causes of FTD. Research on these mutations will help to identify effective therapies. However, the ability to study the functions of these factors is severely limited due to the lack of available human neurons from FTD patients. To address the need for diseaseó and patientóspecific neurons, we will use the powerful new technique of iPS cells. iPS cells are derived from skin cells and can be used to generate any cell types in the body, including neurons. We will obtain human skin cells from FTD patients with disease-causing mutations and generate many FTD mutationóspecific iPS cell lines. We will then use these iPS cells to generate FTD mutationóspecific neurons to study disease mechanisms. The bank of iPS cell lines we generate will also enable the development of sensitive assays for drug screening and testing of therapeutic agents for treating FTD. All cell lines will be made available to the global FTD research community. The generation of human neurons from FTD patients will be a tremendous advance toward finding a cure for this disease. MicroRNAs in Human Stem Cell Differentiation and Mental Disorders 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 21ñ22 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.

 
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