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.

项目摘要： 胎儿或透明的血管系统在眼部发育过程中滋养镜头和视网膜，随后 在形成残留视频后退缩。胎儿脉管系统失败导致严重 视力问题，一种称为持续性胎儿脉管系统（PFV）疾病的疾病。确切的普遍性 PFV是未知的；但是，美国关于儿童失明和视觉丧失的研究表明 PFV占所有儿童失明案件的5％。我们以前关于PFV研究的重大发现是 星形胶质细胞绝对迁移到玻璃体和透明动脉下方，这表明直接原因 星形胶质细胞关联与血管保留之间的关系。星形胶质细胞不知道 参与透明动脉的形成或回归。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透明膜的外观有关 动脉。除了我们已经研究的那些鼠标，PFV的几种鼠标模型似乎都有星形胶质细胞 与持续的透明动脉相关。重要的是，我们还表明星形胶质细胞异常 在PFV患者的临床规格中汇总透明动脉。 PFV涉及组件的持久性 正常瞬时胎儿的人类脉管系统，并且可以在完整性和 严重程度。玻璃体中增加的血管内皮生长因子（VEGF）肯定是重要的 严重PFV病因的因素，在轻度或中度PFV中可能并非如此。我们的重点 是为轻度/中度疾病开发一种疗法。 PFV是一种复杂且异质性疾病，没有单一疾病 治疗可能对所有患者有效。适当的治疗很可能取决于疾病的严重程度。 患有严重疾病，有纤维性茎，如果在此之前给出的药物，我们在这里开发的药物可能会有效 玻璃体切除术，类似于抗VEGFA注射剂在玻璃体切除术之前进行糖尿病牵引力脱离 通过减少术中和术后出血，使手术在技术上变得更简单。我们在这里 将检验以下假设：“恢复正常的星形胶质细胞功能是有效的治疗策略 PFV疾病”。该目标将通过追求以下特定目的来实现：特定目的1： 为了证明a1-晶状体过表达是否可以恢复星形胶质细胞功能，从而挽救了该功能 PFV样表型；特定目标2：测试是否抑制吉非替尼并激活自噬溶酶体 改革触发了透明脉管系统的正常回归和特定目的3：确定因素 由A1KD星形胶质细胞释放，可以抑制胎儿正常发育重塑（回归） 脉管系统。拟议的研究很重要，因为我们现在有适当的动物模型来测试 根据我们的研究，新颖的治疗方法来治疗PFV。显然，大多数患有PFV的孩子 视觉结果差。因此，即使只有少数患者从 治疗，这仍然是重要的治疗进展。