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发育期间覆盖透镜和视网膜，随后 在视网膜血管形成后退化。胎儿脉管系统的退化失败导致严重的 视力问题，一种被称为持续性胎儿血管系统（PFV）疾病的疾病。确切的患病率 PFV是未知的;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中并包裹玻璃体动脉，这表明 以及星形胶质细胞联合与血管潴留之间的关系。目前尚不清楚星形胶质细胞是否 参与玻璃体动脉的形成或消退。我们的数据显示， 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化的增加有关 动脉除了我们已经研究过的，几种PFV小鼠模型似乎有星形胶质细胞 与玻璃体动脉相连重要的是，我们还发现星形胶质细胞异常地 在PFV患者的临床标本中包裹玻璃体动脉。PFV涉及组件的持久性 通常短暂的胎儿眼内血管系统，并可以在完整性方面变化很大， 严重性。虽然玻璃体中血管内皮生长因子（VEGF）的增加肯定是一个重要的因素， 在重度PFV的病因学中，它可能不是轻度或中度PFV的情况。我们在本提案中的重点 是开发一种治疗轻度/中度疾病的方法。PFV是一种复杂的异质性疾病， 治疗可能对所有患者有效。适当的治疗可能取决于疾病的严重程度。 对于纤维化茎的严重疾病，我们在这里开发的药物可能是有效的，如果在 玻璃体切除术，类似于在糖尿病牵引脱离的玻璃体切除术前给予抗VEGFA注射 使手术技术更简单，减少术中和术后并发症。这里我们 将测试假设，“恢复正常的星形胶质细胞功能是一种有效的治疗策略， PFV病”。这一目标将通过实现以下具体目标来实现：具体目标1： 为了证明过表达β-A1-晶状体蛋白是否可以恢复星形胶质细胞的功能，从而挽救星形胶质细胞的功能， PFV样表型;具体目的2：检测是否抑制吉非替尼并激活自噬溶酶体 重建触发玻璃体血管的正常消退，具体目标3：确定因素 由能抑制胎儿正常发育重塑（退化）的CD 1A 1 KD星形胶质细胞释放 脉管系统这项拟议中的研究意义重大，因为我们现在有合适的动物模型进行测试 新的治疗方法来治疗PFV的基础上，我们的研究。很明显，大多数患有PFV的儿童 视觉效果不佳。因此，即使只有少数患者显著受益于 治疗，它仍然是一个重要的治疗进展。