The goals of the Neurogenetics Center are to elucidate the molecular etiology of several inherited neurologic diseases, are means of gene transfer into the nervous system. Research on diseases will proceed through several levels of investigation. 1) Finding disease genes. Linkage studies using highly polymorphic DNA probes and multipoint analysis undertaken to search the genome for the genes responsible for Batten disease (neuronal ceroid lipofusconosis NCL), tuberous sclerosis, and familial dysautonomia (Riley-Day syndrome). Extensive pedigrees have collected by this center and initial work will focus on confirming possible linkage for NCL on chromosome 16 and for tuberous sclerosis on chromosomes 9 and 11. Because linkage analysis relies critically on re diagnosis of family members, this search will continue to be backed up by extensive clinical, genetic, neuroimaging analyses to establish diagnosis and to investigate the possible genetic heterogeneity of NC tuberous sclerosis. 2) Characterizing disease genes. For neurofibromatosis type 2 (NF2), molecular genetic methods will be us proceed from tightly linked, flanking markers to identification of this tumor-suppressor gene; biochemical cell biological methods will then be employed to characterize the structure and function of the responsible protein. MRI neuroimaging of the brains of NF patients will be used to elucidate possible neurodevelopmental anomalies, as well as initiation and rate of tumor growth over time. For NCL, extensive biochemical analyses will be carried out to characterize lipid-linked oligosaccharide storage products in different forms of the disease as clues to the defective gene(s). Activities of candidate synthetic and degradative enzymes involved in glycoprotein and glycolipid metabolism will also be measured in cells and brain tissue from patients. 3) Gene transfer to the nervous system. Therapy win ultimately come from delivering corrective genes neural cells. The introduction of genes into cells of the nervous system has a number of applications in terms of elucidating the function of genes and altering the physiology of neural cells. Two applications employing gene delivery to the somatic rodent nervous system will be explored here. Delivery will be via grafting genetically modified cells and direct inoculation of retrovirus and herpes virus vectors. Genes to be delivered will be the histochemical marker gene lac Z, several forms of basic fibroblast growth factor (bFGF), and the herpes simplex virus (HSV), thymidine kinase (TK) gene. The effects of the latter two genes will be assessed on growth and death of neural tumor cells, and on neurite regeneration and selective death of sensory neurons. High resolution imaging of rodent brain will be developed to follow tumor growth in the same animal over time. Collectively these studies provide a comprehensive approach to the study of NCL, neurofibromatosis, tuberous sclerosis, familial dysautonomia and tumors of the nervous system using state-of-the-art molecular ge techniques.
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