Function of a lens protein betaA3/A1-crystallin in astrocytes

星形胶质细胞中晶状体蛋白 betaA3/A1-晶状体蛋白的功能

• 批准号: 10366476
• 负责人: DEBASISH SINHA
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366476
• 关键词: 3-Dimensional; Animal Model; Apoptosis; Arteries; Astrocytes; Autophagocytosis; Blindness; Blood Vessels; Cell Death; Characteristics; Child; Childhood; Clinical; Combined Modality Therapy; Complex; Crystallins; Data; Deletion Mutation; Development; Disease; Endothelial Cells; Ensure; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Etiology; Eye; Eye Development; FRAP1 gene; Failure; Gefitinib; Goals; India; Inherited; Injections; Knockout Mice; Lead; Link; Lysosomes; Minority; Modality; Monitor; Mus; Operative Surgical Procedures; Orphan; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Postoperative Hemorrhage; Prevalence; Process; Protein Isoforms; Proteins; Publishing; Rare Diseases; Resolution; Retina; Retinal Degeneration; Scanning; Severities; Severity of illness; Site; Specimen; Supporting Cell; Testing; Therapeutic; Tissues; Traction; Transgenic Mice; United States; VEGFA gene; Vascular Endothelial Growth Factors; Vision; Visual; Vitrectomy; base; cohort; diabetic; dietary; fetal; functional loss; gene therapy; in vivo Model; knock-down; lens; migration; mouse model; mutant; novel therapeutic intervention; overexpression; promoter; reconstruction; release factor; retina blood vessel structure; therapeutic target; therapeutically effective; transcription factor

Project Summary: The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after the formation of retinal vessels. The failure of the fetal vasculature to regress leads to serious problems with vision, a condition known as persistent fetal vasculature (PFV) disease. The exact prevalence of PFV is unknown; however, a study on childhood blindness and visual loss in the United States showed that PFV accounts for 5% of all childhood cases of blindness. A major finding from our previous studies on PFV is that astrocytes abnormally migrate into the vitreous and ensheath the hyaloid artery, suggesting a direct cause and effect relationship between astrocyte association and vascular retention. Astrocytes are not known to be involved in either the formation or regression of the hyaloid artery. Our data suggested that the defective lysosomal function in astrocytes is linked to increased astrocyte migration and ensheathment of the hyaloid artery. Several mouse models of PFV, in addition to those we have studied, appear to have astrocytes associated with the persistent hyaloid artery. Importantly, we have also shown that astrocytes abnormally ensheath the hyaloid artery in clinical specimens from PFV patients. PFV involves persistence of components of the normally transient fetal intraocular vasculature and can vary widely in terms of completeness and severity. While increased vascular endothelial growth factor (VEGF) in the vitreous is certainly an important factor in the etiology of severe PFV, it is likely not the case in mild or moderate PFV. Our focus in this proposal is to develop a therapy for mild/moderate disease. PFV is a complex and heterogeneous disease and no single therapy is likely to be effective for all patients. Appropriate treatment may well depend upon disease severity. With severe disease with a fibrotic stalk, the drug(s) that we develop here may be efficacious if given prior to vitrectomy, analogous to anti-VEGFA injections being given prior to vitrectomy for diabetic traction detachment to make the surgery technically simpler with reduced intraoperative and postoperative hemorrhaging. Here we will test the hypothesis that “restoring normal astrocyte function is an effective therapeutic strategy for PFV disease”. This objective will be accomplished by pursuing the following Specific Aims: Specific Aim 1: To demonstrate if A1-crystallin overexpression can rejuvenate astrocyte function and thereby rescue the PFV-like phenotype; Specific Aim 2: To test if inhibiting gefitinib and activating autophagic lysosomal reformation triggers normal regression of the hyaloid vasculature and Specific Aim 3: To identify factors released by A1 KD astrocytes that could inhibit normal developmental remodeling (regression) of the fetal vasculature. The proposed study is significant because we now have the appropriate animal models to test novel therapeutic approaches to treat PFV based on our studies. It is apparent that most children with PFV have a poor visual outcome. Therefore, even if only a minority of patients significantly benefit from the treatment, it would still be an important therapeutic advance.

项目概要： 胎儿或玻璃体脉管系统在眼睛发育过程中滋养晶状体和视网膜，随后 视网膜血管形成后退化 胎儿血管系统退化失败会导致严重的后果。 视力问题，一种称为持续性胎儿脉管系统（PFV）疾病的确切患病率。 PFV 尚不清楚；然而，美国一项关于儿童失明和视力丧失的研究表明： PFV 占所有儿童失明病例的 5%。 我们之前关于 PFV 的研究的一个主要发现是。 星形胶质细胞异常迁移到玻璃体并包裹玻璃体动脉，这表明直接原因 星形胶质细胞关联与血管滞留之间的影响关系尚不清楚。 参与玻璃体动脉的形成或退化我们的数据表明有缺陷。 星形胶质细胞中的溶酶体功能与星形胶质细胞迁移和玻璃体鞘的增加有关 除了我们研究过的模型外，几种 PFV 小鼠模型似乎也含有星形胶质细胞。 重要的是，我们还发现星形胶质细胞异常。 在 PFV 患者的临床标本中包裹玻璃体动脉涉及成分的持续存在。 胎儿眼内脉管系统的正常短暂性，在完整性和完整性方面可能存在很大差异 而玻璃体中血管内皮生长因子（VEGF）的增加无疑是一个重要因素。 重度 PFV 的病因学因素，但轻度或中度 PFV 的情况可能并非如此。 PFV 是一种复杂且异质的疾病，而不是单一的疾病。 治疗可能对所有患者都有效，适当的治疗很可能取决于疾病的严重程度。 对于伴有纤维化柄的严重疾病，如果在治疗之前给予，我们在此开发的药物可能会有效。 玻璃体切除术，类似于在糖尿病牵引脱离玻璃体切除术之前注射抗 VEGFA 使手术在技术上更简单，减少术中和术后出血。 将检验“恢复正常星形胶质细胞功能是一种有效的治疗策略”的假设 该目标将通过追求以下具体目标来实现： 具体目标 1： 证明 A1-晶状体蛋白过度表达是否可以恢复星形胶质细胞功能，从而挽救 PFV样表型；具体目标2：测试吉非替尼是否抑制并激活自噬溶酶体 重组触发玻璃体脉管系统的正常消退和具体目标 3：确定因素 由 A1 KD 星形胶质细胞释放，可以抑制胎儿的正常发育重塑（回归） 拟议的研究意义重大，因为我们现在有合适的动物模型来测试。 根据我们的研究，治疗 PFV 的新治疗方法 显然，大多数患有 PFV 的儿童。 因此，即使只有少数患者能从该治疗中显着受益。 治疗，这仍然是一个重要的治疗进展。