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Role of Abnormal lysyl oxidase in the pathogenesis of diabetic retinopathy

赖氨酰氧化酶异常在糖尿病视网膜病变发病机制中的作用

基本信息

批准号：
8911490
负责人：
Sayon Roy
金额：
$ 43.5万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911490
关键词：
Affinity Age Apoptosis Attenuated Basement membrane Binding Biochemical Biogenesis Blindness Blood Vessels Blood capillaries Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Cell physiology Cells Characteristics Clinical Clinical Trials Data Development Diabetes Mellitus Diabetic Retinopathy Disease Endothelial Cells Enzyme Precursors Enzymes Extracellular Matrix Extravasation FGF2 gene Feedback Fibronectins Figs - dietary Glucose Goals Human In Vitro Incidence Inhibition of Apoptosis Lead Lesion Literature Maps Mediating Modality Molecular Genetics Mus Pathogenesis Pathway interactions Patients Pericytes Permeability Phosphotransferases Population Prevalence Process Protein Isoforms Protein-Lysine 6-Oxidase Proteins Public Health Research Retina Retinal Role Signal Transduction Testing Up-Regulation Vascular Permeabilities Work animal facility base capillary crosslink diabetic diabetic rat extracellular genetic approach insight monolayer novel therapeutics overexpression prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to test the hypothesis that increased lysyl oxidase (LOX) expression and activation triggered by high glucose/diabetes compromises basement membrane (BM) function and thereby induces excess permeability and vascular cell death in diabetic retinopathy (DR). The hypothesis is based on findings that diabetes increases expression of LOX, which is required for the formation and maturation of the BM, and that HG-induced LOX upregulation and over-activation compromises endothelial barrier function. Importantly, inhibition of HG-induced LOX overexpression results in reduced cell monolayer permeability. While LOX is known for its cross-linking activity, LOX propeptide (LOX-PP), released during LOX biogenesis, is known for regulating cell proliferation and survival through modulation of Akt and Erk pathways. Our preliminary data indicates that HG-induced LOX overexpression promotes apoptosis in retinal endothelial cells, and that the process may be exacerbated by LOX-PP, which is upregulated by HG. Furthermore, preliminary data indicates that LOX binds with high affinity to extracellular fibronectin (FN) under HG condition, and interferes with LOX internalization into the cell, a process unique to LOX. Thus, the rationale for the proposed studies is that (i) HG-induced LOX overexpression contributes to capillary leakage, and together with increased LOX-PP promotes apoptosis by modulating Akt and Erk pathways, and (ii) HG-induced increased binding of LOX with ECM proteins, decreases LOX internalization, attenuates negative feedback signaling and thereby promotes LOX overexpression. The proposed studies will be performed using biochemical, molecular, and genetic approaches utilizing cell culture models, diabetic rats, and LOX heterozygous KO mice (LOX+/-). Towards this goal, we have generated LOX+/- mice colonies at our animal facility that are now available for the proposed studies. The specific aims of this proposal are to determine (i) whether inhibition of LOX overexpression and activation prevents apoptosis in retinal endothelial cells in vitro, and reduces vascular cell loss and permeability in diabetic rat retinas (ii) whether the decreased LOX level in LOX+/- mice is protective against diabetes-induced retinal vascular lesions, and (iii) mechanism(s) by which HG induces LOX overexpression and promotes retinal vascular cell loss. Findings from these studies are expected to identify a novel therapeutic strategy for preventing retinal vascular cell loss and capillary leakage, and provide mechanistic insights underlying HG-induced LOX overexpression in DR.