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National Institute on Aging
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Research Programs

Human Genetics Section
David Schlessinger, Ph.D., Chief
Senior Investigator
Overview: The program is designed to study embryonic and developmental events critical for the aging of specialized mammalian cells and concomitant aging-related phenomena. The program includes:
1. Studies at the level of gene regulation in chromatin. Projects are designed to understand tissue- and developmentally-restricted expression of two genes, one that when mutated causes inherited premature ovarian failure (see below), and another that is placental-specific (PLAC1) and possibly involved in fetal well-being. Promoter and enhancer element functions are being analyzed in those instances. The regulatory processes involve features of chromatin; analyses of open and closed chromatin are projected for the genes recovered in chromatin form in artificial chromosomes in the Gene Recovery and Analysis Unit, headed by Ramaiah Nagaraja.
2. Cohorts of genes involved in selected processes, using a "genome approach" to developmental phenomena. The approach starts from human inherited conditions and relevant embryological studies in mouse models (where sets of genes from embryonic stages can be easily assessed, and knockout technologies are available). Examples include:
  • Premature ovarian failure. A subset of women with premature ovarian failure (POF) have a defect that is also associated with eyelid dysplasia (BPES, the blepharophimosis-ptosis-epicanthus inversus syndrome). We have identified a "winged helix" transcription factor, FOXL2, that is mutated to cause both the eyelid and ovarian follicle defects. In correlated developmental work, a mouse knockout model has been developed that recapitulates features of BPES, and systematic studies are under way of gene cohorts specifically expressed during the development of ovarian follicles, including the target genes controlled by FOXL2.
  • Skin appendage formation. The gene mutated in X-linked anhidrotic ectodermal dysplasia (EDA) provides an entree to an embryonic branch point that leads to teeth, hair follicles, and sebaceous and sweat glands. The Tabby mouse has been shown to be an experimental model for the human condition, and interacting genes can be found both by genomic approaches and by genetic studies of some of the other 175 inherited ectodermal dysplasias. Transgenic Tabby animals containing various isoforms of the EDA protein are revealing both the capacity of isoforms to initiate or maintain the restoration of some skin appendages, and to sustain the hyperproliferation of others.
The projected work will depend on the Gene Recovery and Analysis Unit, directed by Ramaiah Nagaraja, and collaborating groups. Related efforts are studying the genetic potential in the embryo-regulatory t-complex region of the mouse; and more directly relevant to human conditions, an extensive project is studying a favorably inter-related population in Sardinia to determine critical genes involved in aging-related traits, with the long-term aim of promoting patient benefit.
Another group adapting new technology, the Image Informatics and Computational Biology Unit headed by Ilya Goldberg is helping to complete the range of necessary technology for functional genomics by developing quantitative visual assays. The unit is principal developer and co-founder of the Open Microscopy Environment (OME) project. OME is a software package and a set of standards for image informatics - the collection, maintenance, and analysis of biological images and associated data. The aim of this project is to standardize how image information is stored, extracted and transported between different software applications. In pilot work, current versions of OME have addressed applications of high-resolution imaging to track intracellular particles in real time, and screening applications involving hundreds of thousands of images. Currently, the group is continuing to develop relevant computational tools and information systems, and to apply them to two specific biological areas: determining the spatial distribution of differentially expressed gene products in pre-implantation mouse embryos, and visual screening of populations of the nematode C. elegans in which one gene is inactivated at a time across the genome.
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Updated: Thursday April 22, 2010