The lens is an unusual organ, containing three different cell types. One types does not divide but survives throughout life (central epithelial cells) another consists of dividing cells (epithelial cells in the mitotic zone), & the third is made up of enucleated fiber cells. Survival of central lens epithelial cells (LECs) may require continuous signaling by factors from LECs or other cells. Although most vertebrate cells require growth factors for their growth and proliferation during development, little is known about survival of mature central LECs A novel growth and survival factor was isolated from a human lens epithelial cell cDNA library with auto-antibodies (auto-Abs) cytocidal for LECs and named it lens epithelium-derived growth factor (LEDGF). As a growth factor LEDGF has both autocrine and paracrine effects on LECs, skin fibroblasts, and keratinocytes. It is secreted by the cell, binds to the cell surface, localizes in the nucleus, & regulates protein synthesis. LEDGF is a survival factor for the various cell types against heat- stress, serum starvation-stress, and oxidative-stress, in that the aforementioned cells do not survive without LEDGF. A basic mechanism of cellular survival against these stresses may be an elevated expression of the heat shock proteins (Hsps) 27 and alphaB-crystallin. Abs to LEDGF are prevalent in human sera, and neutralization of LEDGF by auto-Abs blocks cell growth and eventually leads to cell death. We speculate that death of epithelial cells and fibroblasts following the depletion of LEDGF by auto- Abs may be a risk factor for age-related cataract.. This research proposal comprises five aims. 1) To further establish LEDGF as a growth and survival factor for variety of cell types. 2) To determine functionally important sites in LEDGF. 3) To isolate the receptor of LEDGF and determine amino acid sequence. 4) To study expression and regulation of LEDGF and its receptor genes. 5) To investigate the mechanisms of survival of LECs in the presence LEDGF and of death of LECs in its absence. Studying the basic role of LEDGF in survival and death of LECs can enhance our standing of aging including development, growth, and age- related cataract.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences A Study Section (VISA)
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Liberman, Ellen S
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Brigham and Women's Hospital
United States
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Ayaki, Masahiko; Ohoguro, Nobuyuki; Azuma, Noriyuki et al. (2002) Detection of cytotoxic anti-LEDGF autoantibodies in atopic dermatitis. Autoimmunity 35:319-27
Nishizawa, Y; Usukura, J; Singh, D P et al. (2001) Spatial and temporal dynamics of two alternatively spliced regulatory factors, lens epithelium-derived growth factor (ledgf/p75) and p52, in the nucleus. Cell Tissue Res 305:107-14
Matsui, H; Lin, L R; Singh, D P et al. (2001) Lens epithelium-derived growth factor: increased survival and decreased DNA breakage of human RPE cells induced by oxidative stress. Invest Ophthalmol Vis Sci 42:2935-41
Nakamura, M; Singh, D P; Kubo, E et al. (2000) LEDGF: survival of embryonic chick retinal photoreceptor cells. Invest Ophthalmol Vis Sci 41:1168-75
Sharma, P; Singh, D P; Fatma, N et al. (2000) Activation of LEDGF gene by thermal-and oxidative-stresses. Biochem Biophys Res Commun 276:1320-4
Fatma, N; Singh, D P; Shinohara, T et al. (2000) Heparin's roles in stabilizing, potentiating, and transporting LEDGF into the nucleus. Invest Ophthalmol Vis Sci 41:2648-57
Singh, D P; Kimura, A; Chylack Jr, L T et al. (2000) Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. Gene 242:265-73
Ayaki, M; Sueno, T; Singh, D P et al. (1999) Antibodies to lens epithelium-derived growth factor (LEDGF) kill epithelial cells of whole lenses in organ culture. Exp Eye Res 69:139-42
Singh, D P; Sueno, T; Kikuchi, T et al. (1999) Antibodies to a microbial peptide sharing sequence homology with betaA3-crystallin damage lens epithelial cells in vitro and in vivo. Autoimmunity 29:311-22
Singh, D P; Ohguro, N; Chylack Jr, L T et al. (1999) Lens epithelium-derived growth factor: increased resistance to thermal and oxidative stresses. Invest Ophthalmol Vis Sci 40:1444-51

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