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

项目总结： 胎儿或玻璃体血管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。胎儿血管系统的失败会导致严重的 视力问题，一种被称为持续性胎儿血管疾病(PFV)的疾病。疾病的确切流行率 PFV尚不清楚；然而，一项关于美国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%。我们以前对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，提示有直接原因 星形胶质细胞联合与血管滞留的作用关系。星形胶质细胞是未知的 与玻璃体动脉的形成或消退有关。我们的数据显示有缺陷的 星形胶质细胞的溶酶体功能与星形胶质细胞迁移和玻璃体包裹的增加有关 动脉。除了我们已经研究过的模型外，几种PFV小鼠模型似乎都有星形胶质细胞。 与永存的玻璃体动脉相关。重要的是，我们还证明了星形胶质细胞的异常 肺静脉瘘患者临床标本中的玻璃体动脉鞘。PFV涉及组件的持久化 正常短暂的胎儿眼内血管系统，在完整性和可变性方面差异很大 严肃性。而玻璃体中血管内皮生长因子(VEGF)的增加肯定是一个重要的 在重度PFV的病因中，在轻度或中度PFV中可能不是这样。我们在这项提案中的重点是 就是开发一种治疗轻/中度疾病的方法。PFV是一种复杂的异质性疾病，并不是单一的 治疗很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。 对于严重的纤维性柄疾病，我们在这里开发的药物(S)如果提前给药可能是有效的 玻璃体切除，类似于糖尿病牵引脱离玻璃体切除前注射抗VEGFA 以减少术中和术后出血，使手术在技术上更简单。在这里我们 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”的假说 PFV病“。这一目标将通过追求以下具体目标来实现：具体目标1： 为了证明A1-晶体蛋白过表达是否可以恢复星形胶质细胞的功能，从而拯救 PFV样表型；特异性目标2：检测是否抑制吉非替尼和激活自噬溶酶体 改革触发玻璃体血管的正常退化和特定目标3：确定因素 由A1 kD星形胶质细胞释放，可抑制胎儿正常发育重塑(退化) 脉管系统。这项拟议的研究意义重大，因为我们现在有了合适的动物模型来测试 根据我们的研究，治疗PFV的新的治疗方法。显然，大多数患有PFV的儿童 视觉效果很差。因此，即使只有一小部分患者从 治疗方面，这仍将是一个重要的治疗进展。

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.