期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 16, 页码 4584-4598出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv189
关键词
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资金
- National Institute of Health [K08EY020530, R01EY024665, R01EY025225, R01EY018213, 5T32EY013933, 5T32DK007647-20]
- National Institute of Health (Doris Duke Charitable Foundation) [2013103]
- Research to Prevent Blindness NewYork, NY, USA
- National Institute of Health Core [5P30EY019007]
- National Cancer Institute Core [5P30CA013696]
- Research to Prevent Blindness, New York, NY, USA
- Tistou and Charlotte Kerstan Foundation
- Research to Prevent Blindness Physician-Scientist Award
- Schneeweiss Stem Cell Fund, New York State [N09G-302, N13G-275]
- Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]
- Joel Hoffman Fund
- Gale and Richard Siegel Stem Cell Fund
- Charles Culpeper Scholarship
- Laszlo Bito and Olivia Carino Foundation
- Irma T. Hirschl Charitable Trust
- Bernard and Anne Spitzer Stem Cell Fund
- Professor Gertrude Rothschild Stem Cell Foundation
- Gebroe Family Foundation
- National Cancer Institute [F32CA196065]
A single amino acid mutation near the active site of the CAPN5 proteasewas linked to the inherited blinding disorder, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #193235). In homology modeling with other calpains, this R243L CAPN5 mutation was situated in a mobile loop that gates substrate access to the calcium-regulated active site. In in vitro activity assays, the mutation increased calpain protease activity and made it far more active at low concentrations of calcium. To test whether the disease allele could yield an animal model of ADNIV, we created transgenic mice expressing human (h) CAPN(5R243L) only in the retina. The resulting hCAPN5(R243L) transgenic mice developed a phenotype consistent with human uveitis and ADNIV, at the clinical, histological and molecular levels. The fundus of hCAPN5(R243L) mice showed enhanced autofluorescence (AF) and pigment changes indicative of reactive retinal pigment epithelial cells and photoreceptor degeneration. Electroretinography showed mutant mouse eyes had a selective loss of the b-wave indicating an inner-retina signaling defect. Histological analysis of mutant mouse eyes showed protein extravasation from dilated vessels into the anterior chamber and vitreous, vitreous inflammation, vitreous and retinal fibrosis and retinal degeneration. Analysis of gene expression changes in the hCAPN5(R243L) mouse retina showed upregulation of several markers, including members of the Toll-like receptor pathway, chemokines and cytokines, indicative of both an innate and adaptive immune response. Since many forms of uveitis share phenotypic characteristics of ADNIV, this mouse offers a model with therapeutic testing utility for ADNIV and uveitis patients.
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