Investigating Membrane Trafficking Deficits in Choroideremia

摘要：脉络膜死亡，脉络膜是视网膜下的血管床，是视网膜的显著病理特征。 许多遗传性视网膜退行性疾病以及老年性黄斑变性(AMD)。 脉络膜死亡可能受到视网膜色素上皮(RPE)功能障碍的影响，RPE是单层细胞 光感受器和脉络膜之间。阻碍治疗进展的关键知识鸿沟 策略是RPE功能障碍如何导致脉络膜死亡。脉络膜病是一种遗传性脉络膜视网膜病变 退化导致早期失明，没有目前的治疗方法。有几条证据表明RPE与 为原发变性部位，继发于光感受器和脉络膜。这个 致病基因缺陷是编码Rab护送蛋白1(rep-1)的CHM缺乏，这有助于 Rab GTP酶的预烯基化，膜转运的关键步骤。RPE细胞高度极化， 定向分泌多种生长因子和信号分子 光感受器和脉络膜。拟议的研究将阐明RPE膜转运缺陷是如何在 脉络膜血症改变蛋白质分泌，以及这如何影响脉络膜存活。这项工作的长期目标是 是发展必要的技能和专业知识，以建立专注于治疗的独立职业生涯 针对视网膜退行性疾病的RPE功能障碍。科学的目标是理解 脉络膜死亡的机制。我们将检验这样一种假设，即RPE分泌的蛋白质在 使用人类干细胞来源的RPE研究脉络膜血症患者脉络膜萎缩的血管存活途径 模特。职业发展目标是掌握干细胞培养和RPE衍生技术，以 发展RPE膜转运途径方面的专业知识，以熟练掌握技术和 发现治疗靶点的原则，以及发展领导、指导和科学的技能 成为一名成功的独立调查员所必需的沟通。拟议的研究将增加 候选人对脉络膜血症的理解，并在这种无法治愈的失明中确定治疗靶点 疾病也可能对AMD和其他脉络膜视网膜的脉络膜变性有更广泛的影响 退行性疾病。

SUMMARY: Death of the choroid, the vascular bed underlying the retina, is a prominent pathologic hallmark of numerous inherited retinal degenerative diseases as well as age-related macular degeneration (AMD). Choroidal death is likely impacted by dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells between the photoreceptors and the choroid. A critical knowledge gap impeding progress in therapeutic strategies is how RPE dysfunction contributes to choroidal death. Choroideremia is an inherited chorioretinal degeneration leading to early blindness with no current treatment. Several lines of evidence implicate the RPE as the primary site of degeneration, with secondary degeneration of the photoreceptors and choroid. The causative genetic defect is deficiency of CHM, encoding Rab escort protein 1 (REP-1), which facilitates prenylation of Rab GTPases, a critical step in membrane trafficking. RPE cells are highly polarized and differentially secrete numerous growth factors and signaling molecules in a directional manner towards the photoreceptors and choroid. The proposed studies will elucidate how RPE membrane trafficking defects in choroideremia alter protein secretion and how this impacts choroidal survival. The long-term goal of this work is to develop the necessary skills and expertise to establish an independent career focused on therapies targeting RPE dysfunction in retinal degenerative disease. The scientific objective is to understand mechanisms of choroidal death. We will test the hypothesis that alterations in RPE secretion of proteins in the vascular survival pathway lead to choroidal atrophy in choroideremia using a human stem cell derived RPE model. The career development objectives are to master stem cell culture and RPE derivation techniques, to develop expertise in membrane trafficking pathways of RPE, to become proficient in the techniques and principles of therapeutic target discovery, and to develop skills in leadership, mentorship, and scientific communication necessary to become a successful independent investigator. The proposed study will increase the candidate’s understanding of choroideremia and identify therapeutic targets in this untreatable blinding disease, which may also have broader implications for choroidal degeneration in AMD and other chorioretinal degenerative diseases.