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Targeting peptide Lv and its downstream signaling against ocular neovascularization

靶向肽 Lv 及其下游信号对抗眼部新生血管形成

基本信息

批准号：
10407598
负责人：
GLADYS Y KO
金额：
$ 21.62万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407598
关键词：
Age related macular degeneration Angiogenic Factor Angiogenic Peptides Animal Model Antibodies Binding Biological Assay Blindness Blood Vessels Blood flow Calcium Cell Proliferation Choroidal Neovascularization Chronic Clinical Data Development Disease Endothelial Cells Endothelial Growth Factors Receptor Endothelium Extravasation Family Future Genetic Goals In Vitro Incidence KDR gene Knock-out Knowledge L-Type Calcium Channels Lasers Lead Mediating Messenger RNA Mission Molecular Mus Muscle Cells Nitric Oxide Nitric Oxide Synthetase Inhibitor Oxygen Pathogenesis Pathologic Pathologic Neovascularization Patients Peptides Pharmacology Photoreceptors Pilot Projects Potassium Channel Prevention Property Recurrence Research Resistance Retina Retinal Detachment Retinal Diseases Role Sequence Homology Signal Transduction Smooth Muscle Testing Therapeutic Treatment Factor United States National Institutes of Health Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Vasodilation Vasodilator Agents Veins angiogenesis arteriole combat in vivo member migration mouse model mutant neovascular neovascularization novel ocular angiogenesis ocular neovascularization proliferative diabetic retinopathy protein expression resistance mechanism side effect tool

项目摘要

Project Summary Anti-vascular endothelial growth factor (VEGF) therapies are widely used for treating ocular diseases with neovascularization, but nearly 30% of afflicted patients are non-responders to anti-VEGF agents. In addition, repetitive anti-VEGF treatments that are needed to block the recurring neovascularization often lead to unintended side-effects including retinal detachment and even blindness. Thus, searching for VEGF-independent angiogenic factors and unveiling their underlying mechanisms become an imperative clinical need to help combat the recurrence of neovascularization and the resistance to anti-VEGFs in these diseases. Peptide Lv is a newly discovered angiogenic peptide that is upregulated in the retinas of patients with early proliferative diabetic retinopathy (PDR) and of mice subjected to oxygen-induced retinopathy (OIR), featuring ocular pathological neovascularization. Although it has no sequence homology to members of the VEGF family and VEGF receptors (VEGFRs), peptide Lv promotes angiogenesis in vitro and in vivo. An antibody against peptide Lv, anti-Lv, not only dampens VEGF- elicited endothelial cell proliferation, it also effectively blocks pathological neovascularization in mice with OIR, as well as laser-induced choroidal neovascularization. Furthermore, peptide Lv not only cooperatively promotes VEGF-induced angiogenesis, but also elicits VEGF/VEGFR2/nitric oxide-independent vasodilation. Chronic vasodilation of existing vessels causes increased vascular permeability, stimulates angiogenesis, and promotes neovascularization. Vasodilators are associated with a ~70% increased incidence of early age-related macular degeneration (AMD). Thus, peptide Lv might be involved in the pathogenesis of PDR and wet AMD via promoting both VEGF/VEGFR2-dependent and -independent angiogenesis and vasodilation. However, the mechanistic role of peptide Lv in mediating VEGF-independent angiogenesis and vasodilation is completely unknown. Peptide Lv is able to augment the protein expression of intermediate conductance calcium-dependent potassium channels (IKCa) in cultured endothelial cells. Activation of K+ channels in the endothelium, especially IKCa, is important in angiogenesis that can be VEGF/VEGFR2-independent. Opening these K+ channels can also lead to VEGF-independent vasodilation. Herein, the objective is to unveil novel cellular mechanisms of peptide Lv in VEGF/VEGFR2- independent angiogenesis and vasodilation. The central hypothesis is that peptide Lv activates and augments IKCa in retinal endothelial cells that consequently leads to VEGF/VEGFR2-independent angiogenesis and vasodilation, the underlying mechanism of resistance to anti-VEGFs. Two Aims combining in vitro, ex vivo, and in vivo approaches to decipher peptide Lv-IKCa axis in VEGF/VEGFR2-independent angiogenesis and vasodilation will be carried out by using peptide Lv null (peptide Lv-/-), IKCa null (Kcnn4-/-), and vascular endothelial cell-specific knockout of VEGFR2 (VEGFR2iΔEC) mice. Completion of the proposed research will unveil new mechanisms of peptide Lv in VEGF/ VEGFR2-independent angiogenesis and vasodilation, which will have a direct impact on the future development of blocking peptide Lv-downstream targets as a therapeutic tool against ocular pathological neovascularization.

项目总结