Publications by authors named "Lixing Reneker"

Purpose: Fibroblast growth factor receptor 2 (Fgfr2) is crucial for the homeostasis of meibomian gland (MG). However, the role of Fgfr2 in MG ductal epithelial progenitors remains to be delineated. Herein, we created a new transgenic mouse model with conditional deletion of Fgfr2 from MG ductal progenitors and investigated the cell-specific role in the pathogenesis of obstructive meibomian gland dysfunction.

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Meibomian glands (MGs) secrete lipid (meibum) onto the ocular surface to form the outermost layer of the tear film. Proper meibum secretion is essential for stabilizing the tear film, reducing aqueous tear evaporation, and maintaining the homeostasis of the ocular surface. Atrophy of MG as occurs with aging, leads to reduction of meibum secretion, loss of ocular surface homeostasis and evaporative dry eye disease (EDED).

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Purpose: We have demonstrated that deletion of fibroblast growth factor receptor 2 gene (Fgfr2) leads to Meibomian gland (MG) atrophy in an inducible conditional knockout mouse model, referred as Fgfr2. Herein, we investigated whether MG spontaneously recovers after atrophy in this model.

Methods: Two months old Fgfr2 mice were injected peritoneally once or twice of doxycycline (Dox) at 80 μg/gm of body weight to induce MG atrophy of various severities via Fgfr2 deletion.

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Background/aims: Meibomian gland dysfunction (MGD) is the most common form of evaporative dry eye disease, but its pathogenesis is poorly understood. This study examined the histopathological features of meibomian gland (MG) tissue from cadaver donors to identify potential pathogenic processes that underlie MGD in humans.

Methods: Histological analyses was performed on the MGs in the tarsal plates dissected from four cadaver donors, two young and two old adults, including a 36-year-old female (36F) and three males aged 30, 63 and 64 years (30M, 63M and 64M).

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Purpose: Little is known about the signaling mechanisms controlling meibomian gland (MG) homeostasis and the pathogenic processes leading to MG atrophy and dysfunction in dry eye disease (DED). We investigated the role of fibroblast growth factor receptor 2 (FGFR2) in the MG homeostasis of adult mice.

Methods: A triple transgenic mouse strain (Krt14-rtTA; tetO-Cre; Fgfr2flox/flox), referred to as Fgfr2CKO mice, was generated in which the Fgfr2 gene is ablated by Cre recombinase in keratin 14 (Krt14)-expressing epithelial cells on doxycycline (Dox) induction.

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Fibroblast growth factor (FGF) signaling regulates a multitude of cellular processes, including cell proliferation, survival, migration, and differentiation. In the vertebrate lens, FGF signaling regulates fiber cell differentiation characterized by high expression of crystallin proteins. However, a direct link between FGF signaling and crystallin gene transcriptional machinery remains to be established.

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Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous.

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Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated.

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Purpose: Posterior capsule opacification (PCO) after cataract surgery is due in part to proliferation of the adhering lens epithelial cells and transdifferentiation into mesenchymal cells. The histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) and vorinostat (suberoylanilidehydroxamic acid [SAHA]) are known to modulate cell proliferation and epithelial-mesenchymal transition (EMT). Studies have shown that TGFβ2 can induce EMT similar to that seen during PCO.

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The accumulation of crystallin fragments in vivo and their subsequent interaction with crystallins are responsible, in part, for protein aggregation in cataracts. Transgenic mice overexpressing acylpeptide hydrolase (APH) specifically in the lens were prepared to test the role of protease in the generation and accumulation of peptides. Cataract development was seen at various postnatal days in the majority of mice expressing active APH (wt-APH).

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Article Synopsis
  • MAPK1 and MAPK3 are intracellular signaling molecules critical for cell functions, but their roles in lens development differ, with MAPK1 being essential while MAPK3 is not.
  • In experiments using mouse lenses, deletion of MAPK1 leads to reduced cell proliferation specifically in the peripheral lens germinative zone, while the central region is less affected.
  • MAPK1 is vital for cell survival and regulating cyclin D1 and survivin, but not for fiber cell differentiation, highlighting the distinct roles of MAPK1 and the shared functions of MAPK1/3 in lens epithelial cell proliferation.
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Most growth factor receptor tyrosine kinases (RTKs) signal through similar intracellular pathways, but they often have divergent biological effects. Therefore, elucidating the mechanism of channeling the intracellular effect of RTK stimulation to facilitate specific biological responses represents a fundamental biological challenge. Lens epithelial cells express numerous RTKs with the ability to initiate the phosphorylation (activation) of Erk1/2 and PI3-K/Akt signaling.

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Purpose: Overloading of unfolded or misfolded proteins in the endoplasmic reticulum (ER) can cause ER stress and activate the unfolded protein response (UPR) in the cell. The authors tested whether transgene overexpression in the mouse lens would activate the UPR.

Methods: Transgenic mice expressing proteins that either enter the ER secretory pathway or are synthesized in cytosol were selected.

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Objective. Here we tested the role of Glo I in the prevention of advanced glycation end product (AGE) formation in transgenic mouse lenses. Methods.

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Growth factor signaling, mediated via receptor tyrosine kinases (RTKs), needs to be tightly regulated in many developmental systems to ensure a physiologically appropriate biological outcome. At one level this regulation may involve spatially and temporally ordered patterns of expression of specific RTK signaling antagonists, such as Sef (similar expression to fgfs). Growth factors, notably FGFs, play important roles in development of the vertebrate ocular lens.

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Background: Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm.

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Purpose: Transforming growth factor beta (TGFbeta) is an important cytokine in corneal development and wound healing. Transgenic mice that express an active form of human TGFbeta1 driven by a lens-specific promoter were used in the current study to determine the biological effects of lens-derived TGFbeta1 on postnatal corneal development and homeostasis.

Methods: The postnatal corneal changes in the TGFbeta1 transgenic mice were examined by fluorescein labeling and histology.

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Indoleamine 2,3-dioxygenase (IDO) is the first enzyme in the kynurenine pathway. The kynurenines formed in this pathway chemically modify proteins and cause apoptosis in cells. Evidence suggests that kynurenines and their protein modifications are involved in cataract formation, but this has yet to be directly demonstrated.

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To explore the role of the Rho GTPases in lens morphogenesis, we overexpressed bovine Rho GDP dissociation inhibitor (Rho GDI alpha), which serves as a negative regulator of Rho, Rac and Cdc42 GTPase activity, in a lens-specific manner in transgenic mice. This was achieved using a chimeric promoter of delta-crystallin enhancer and alpha A-crystallin, which is active at embryonic day 12. Several individual transgenic (Tg) lines were obtained, and exhibited ocular specific phenotype comprised of microphthalmic eyes with lens opacity.

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Purpose: Insulin and insulin-like growth factors (IGFs) are putative regulators of cell proliferation and differentiation during lens development. Transgenic mice that overexpress IGF-1 in the lens have been previously described. To further understand the ocular functions of this growth factor family, the in vivo effects of insulin expression on lens development were investigated using transgenic mice.

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Senile cataracts are associated with progressive oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. We hypothesized that the Maillard reaction, which leads browning and aroma development during the baking of foods, would occur between the lens proteins and the highly reactive oxidation products of vitamin C. To test this hypothesis, we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens.

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Vitamin C is a major antioxidant and UV absorbent in the human lens. In the rodent lens, the levels are very low for unknown reasons. Searching for clues to explain this suppression, we investigated the comparative uptake of Vitamin C in cultured human and mouse lens epithelial cells.

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The vertebrate ocular lens is a simple and continuously growing tissue. Growth factor-mediated receptor tyrosine kinases (RTKs) are believed to be required for lens cell proliferation, differentiation and survival. The signaling pathways downstream of the RTKs remain to be elucidated.

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Purpose: The chicken embryo lens is a classical model system for developmental and cell biology studies. To understand the molecular mechanisms that underlie the morphological changes that occur during lens development, it is important to develop an effective gene transfer method that permits the analysis of gene functions in vivo. In ovo electroporation has been successfully used for introducing DNA into neural and mesenchymal tissues of chicken embryos.

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Growth factor signaling is implicated in the regulation of lens cell proliferation and differentiation during development. Activation of growth factor receptor tyrosine kinases is known to activate Ras proteins, small GTP-binding proteins that function as part of the signal transduction machinery. In the present study, we examined which classical Ras genes are expressed in lens cells during normal development and whether expression of an activated version of Ras is sufficient to induce either lens cell proliferation or fiber cell differentiation in transgenic mice.

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