Ocular Stem Cells for Vision Recovery

用于视力恢复的眼干细胞

• 批准号: 8925085
• 负责人: Albert Ya-Po Wu
• 金额: $ 21.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925085
• 关键词: Allografting; Animals; Autologous; Bilateral; Biological; Biological Assay; Blindness; Burn Trauma; Cells; Chronic; Cornea; Data; Development Plans; Differentiation Antigens; Disease; Doctor of Philosophy; Embryo; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Eye; Eyelid structure; Fibroblasts; Funding; Goals; Health; Hereditary Disease; Human; Immunosuppression; Infection; Inflammation; Karyotype; Laboratories; Lead; Life; Mentors; Methods; Modeling; Molecular; Monitor; Mono-S; Natural regeneration; Nude Mice; Ophthalmologist; Orbital Diseases; Organ Culture Techniques; Oryctolagus cuniculus; Parents; Patients; Phenotype; Plastic Surgeon; Process; Protocols documentation; Recovery; Regenerative Medicine; Research; Residual state; Sendai virus; Skin; Source; Staging; Stem cells; Surface; Tissue Transplantation; Tissues; Training; Transplantation; Tumorigenicity; Vascularization; Vision; Visual; base; blind; career; career development; corneal epithelial stem cells; corneal scar; epigenetic memory; human tissue; immunosuppressed; improved; in vivo; induced pluripotent stem cell; keratinocyte; limbal; novel; ocular surface; progenitor; research study; stem cell biology; stem cell differentiation; stem cell therapy; stemness

DESCRIPTION (provided by applicant): The candidate is an MD/PhD trained ophthalmologist and ophthalmic plastic surgeon with the career goal of studying stem cells and their application to cure ocular and orbital disease. The career development plan will be jointly mentored by Drs. Ihor Lemishcka and Mario Wolosin. Their laboratories focus of human embryonic and induced pluripotent stem cell biology and corneal limbal stem cells, respectively. The candidate's long-term aim is to understand what controls stem cell differentiation into distinct ocular and orbital tissues, with the goal of creating autologous tissue for transplantation. Over 6 million people worldwide are blind from damage to the ocular surface. Burns, trauma, infection, genetic diseases, and chronic inflammation result in limbal epithelial stem cell deficiency (LSCD) and persistent vision loss from corneal scarring, vascularization and conjunctivalization. Replacement of limbal stem cells is often required to restore vision. In unilateral LSCD cases, the fellow eye is an obvious autologous cell source; in patients with bilateral LSCD (in cases of bilateral blindness) limbal allografts are the only option. For reasons not fully understood, allografts often fail within a few years in these patients despite immunosuppression. Thus, autologous cells are necessary to restore lasting vision. We propose to develop a protocol to generate autologous induced pluripotent stem cell (iPSC)-derived cells capable of acquiring the corneal phenotype in vivo. Our aims are to (1) generate iPSC from cells whose embryological origin is closer to the limbal- corneal lineage, which includes human eyelid skin, and conjunctival and buccal epithelia, (2) differentiate iPSC via progenitor cells using an ectodermal differentiation protocol in combination with soluble factors and limbal niche culture, and (3) assess the ability of the generated cells for ocular surface regeneration using an established human tissue into rabbit model. The funding for this proposal will facilitate the discovery of new stem cell therapies for ocular surface disease and make regenerative medicine a reality for those burdened with blindness.

应聘者描述(由申请人提供)：应聘者是一名受过医学博士和博士学位培训的眼科医生和眼科整形外科医生，其职业目标是研究干细胞及其在治疗眼眶疾病中的应用。职业发展计划将由Ihor Lemishcka博士和Mario Wolosin博士共同指导。他们的实验室分别专注于人类胚胎和诱导多能干细胞生物学和角膜缘干细胞。这位候选人的长期目标是了解是什么控制干细胞分化为不同的眼睛和眼眶组织，目标是创造用于移植的自体组织。全世界有600多万人因眼表受损而失明。烧伤、创伤、感染、遗传性疾病和慢性炎症导致角膜缘上皮干细胞缺乏症(LSCD)和因角膜瘢痕形成、血管形成和结膜形成而导致的持续性视力丧失。通常需要替换角膜缘干细胞来恢复视力。在单侧LSCD病例中，对侧眼是明显的自体细胞来源；对于双侧LSCD患者(在双眼失明的情况下)，同种异体角膜缘移植是唯一的选择。由于不完全了解的原因，在这些患者中，尽管免疫抑制，同种异体移植通常在几年内失败。因此，自体细胞对于恢复持久的视力是必要的。我们建议开发一种方案来产生能够在体内获得角膜表型的自体诱导多能干细胞(IPSC)来源的细胞。我们的目标是(1)从胚胎起源更接近角膜缘-角膜谱系的细胞中产生ipSC，包括人类眼皮和结膜。 (2)采用外胚层分化方案，结合可溶性因子和角膜缘壁龛培养，通过祖细胞向IPSC分化；(3)使用已建立的人组织成兔模型，评估所产生的细胞对眼表再生的能力。这项提案的资金将促进发现治疗眼表疾病的新干细胞疗法，并使再生医学成为盲人的现实。