Investigating Membrane Trafficking Deficits in Choroideremia

脉络膜（视网膜下的血管床）的死亡是视网膜脱离的一个突出的病理标志。 许多遗传性视网膜变性疾病以及年龄相关性黄斑变性（AMD）。 脉络膜死亡很可能受到视网膜色素上皮（RPE）功能障碍的影响， 在感光细胞和脉络膜之间。阻碍治疗进展的关键知识差距 视网膜色素上皮功能障碍如何导致脉络膜死亡。无脉络膜症是一种遗传性脉络膜视网膜病变， 退化导致早期失明，目前没有治疗。有几条证据表明 作为退化的原发部位，伴随着光感受器和脉络膜的继发性退化。的 致病性遗传缺陷是缺乏CHM，编码Rab护送蛋白1（REP-1），这有助于 Rab GTP酶的异戊烯化，这是膜运输的关键步骤。RPE细胞高度极化， 以定向的方式差异性地分泌许多生长因子和信号分子， 光感受器和脉络膜。这些研究将阐明视网膜色素上皮细胞膜运输缺陷是如何影响视网膜色素上皮细胞增殖的。 无脉络膜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，以建立一个独立的职业生涯，专注于治疗 靶向视网膜变性疾病中的RPE功能障碍。科学的目标是了解 脉络膜死亡的机制我们将检验这一假设，即RPE细胞中蛋白质分泌的改变， 使用人干细胞衍生的RPE的血管存活途径导致无脉络膜症中的脉络膜萎缩 模型职业发展目标是掌握干细胞培养和RPE衍生技术， 发展RPE膜运输途径的专业知识，精通技术， 治疗目标发现的原则，并发展领导技能，指导，和科学 成为一名成功的独立调查员所必需的沟通。研究报告将增加 候选人对无脉络膜的理解，并在这种无法治疗的盲法中确定治疗靶点 疾病，这也可能对AMD和其他脉络膜视网膜病变的脉络膜变性有更广泛的影响。 退化性疾病

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.