Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Patent
1997-12-23
2000-01-25
Campell, Bruce R.
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
424 91, 424 92, 435325, 435352, 435357, 800 3, C12N 1500, C12N 1585, A61K 4900, C12Q 100
Patent
active
060180986
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Cutaneous aging results from both intrinsic chronological aging and extrinsic sun-exposure. Montagna et al., J. Am. Acad. Dermatol. 1989, 21:907-918; Kligman, L. H., Aging and the Skin. Raven Press, New York, 1989, pp. 331-346; Taylor et al., J. Am. Acad. Dermatol. 1990, 221:1-15. The majority of changes associated with an aged appearance result from chronic sun-damage. Warren et al., J. Am. Acad. Dermatol. 1991, 25:751-760; Frances, C. and Robert, L., Int. J. Dermatol. 1984, 23:166-179. Dramatic alterations of the superficial dermis accompany the deep wrinkles and laxity common in photoaged skin. The major histopathologic alteration of photoaged skin is the accumulation of material which, on routine histopathologic examination, has the staining characteristics of elastin and is, thus, termed solar elastosis. Immunohistochemical staining has shown the poorly-formed fibers comprising solar elastosis to be composed of elastin (Chen et al., J. Invest. Dermatol. 1986, 87:334-337; Mera et al., Br. J. Dermatol. 1987, 117:21-27) fibrillin (Chen et al., J. Invest. Dermatol. 1986, 87:334-337; Dahlback et al., J. Invest. Dermatol. 1990, 94:284-291; Bernstein et al., J. Invest. Dermatol. 1994, 103:182-186) and versican, the normal components of elastic fibers (Zimmerman et al., J. Cell. Biol. 1994, 124:817-825). A coordinate increase in elastin, fibrillin and versican mRNAs has been demonstrated in fibroblasts derived from photodamaged skin, as compared to fibroblasts derived from normal skin from the same individuals. Bernstein et al., J. Invest. Dermatol. 1994, 103:182-186. Elevated elastin mRNA levels in sun-damaged skin result from enhanced elastin promoter activity, as shown by transient transfections of fibroblasts with a DNA construct composed of the human elastin promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Bernstein et al., J. Invest. Dermatol. 1994, 103:182-186.
A transgenic mouse line which expresses the human elastin promoter/CAT construct has now been developed to further study the role of elastin promoter activation in cutaneous photoaging. These mice express human elastin promoter activity in a tissue-specific and developmentally regulated manner. Promoter activity can be studied in this model as a function of small increases in ultraviolet radiation, demonstrating the sensitivity of the assay. In addition quantitative data can be obtained after only a single exposure to ultraviolet radiation. This transgenic mouse and fibroblasts derived from this mouse are useful as in vivo and in vitro models to study cutaneous photoaging and in the identification of agents which may protect against photodamage.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a transgenic mouse capable of expressing human elastin promoter.
Another object of the present invention is to provide mouse fibroblast cultures derived from a transgenic mouse capable of expressing human elastin promoter.
Method of identifying compounds capable of inhibiting cutaneous photodamage using either the transgenic mouse or fibroblasts derived from these mice are also provided.
DETAILED DESCRIPTION OF THE INVENTION
Profound changes take place in the superficial dermis as a result of chronic sun-exposure. The major alteration is the deposition of massive amounts of abnormal elastic material, termed solar elastosis. It has been shown that solar elastosis is accompanied by elevations in elastin and fibrillin mRNAs and elastin promoter activity. A transgenic mouse model useful as both an in vivo and in vitro model for studying cutaneous photoaging, and for testing compounds that may inhibit cutaneous photodamage has now been developed. Using this transgenic mouse line, which expresses the human elastin promoter linked to a chloramphenicol acetyltransferase (CAT) reporter gene in a tissue-specific and developmentally regulated manner, it is now possible to investigate the effects of ultraviolet A (UVA) and ultraviolet B (UVB) on human elastin promoter activity in
REFERENCES:
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Bernstein Eric F.
Uitto Jouni
Baker Anne-Marie
Campell Bruce R.
Thomas Jefferson University
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