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Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration

Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration
阐明内源性 RPE 再生的分子基础
批准号:
10746951
负责人:
Jeffrey Gross
金额:
$27.59万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-01 至 2024-05-31

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中文摘要
翻译
摘要:导致视网膜色素上皮(RPE)变性的疾病是主要疾病之一
英文摘要
SUMMARY: Diseases resulting in degeneration of the retinal pigment epithelium (RPE) are among the leading causes of blindness worldwide and no therapy exists that can replace RPE or restore lost vision. Age-related macular degeneration (AMD) is one such disease and is the third leading cause of blindness in the world. While there are some effective treatments for exudative (wet) AMD, ~90% of AMD cases are atrophic (dry) and these are currently untreatable. Transplantation of stem-cell derived RPE has emerged as a possibility for treating geographic atrophy and clinical trials are underway. However, little is known about the fate of transplanted RPE and whether their survival and integration can be improved. An intriguing alternative approach to treating AMD and other RPE diseases is to develop therapies focused on stimulating endogenous RPE regeneration. For this to be possible, we must first gain a deeper understanding of the mechanisms underlying RPE regeneration. In mammals, RPE regeneration is extremely limited and in some contexts RPE cells overproliferate after injury, such as during proliferative vitreoretinopathy, where proliferative RPE cells invade the subretinal space and lead to blindness. Recently, a subpopulation of quiescent human RPE stem cells was identified that can be induced to proliferate in vitro and differentiate into RPE or mesenchymal cell types, suggesting that the human RPE contains a population of cells that could be induced to regenerate. Despite these studies, little is known about the process by which RPE cells respond to injury to elicit a regenerative, rather than pathological, response. Indeed, no studies have demonstrated regeneration of a functional RPE monolayer following severe RPE damage in any model system. The development of such a model is a critical first step to acquiring a deeper understanding of the molecular mechanisms underlying RPE regeneration. This knowledge gap is a major barrier to developing effective strategies to restore RPE lost to disease or injury and is the focus of our proposal. We developed a transgenic zebrafish model to study RPE injury and regeneration and demonstrate that the zebrafish RPE regenerates after severe injury. We further demonstrate i) that RPE regeneration involves a robust proliferative response during which proliferative cells move to the injury site and differentiate into RPE, ii) that the source of regenerated cells is likely uninjured peripheral RPE, iii) using this system, we can identify the molecular underpinnings of the regenerative response, and iv) the innate immune system plays a critical role in RPE regeneration. Experiments in this proposal build off of these strong preliminary data to test the hypothesis that RPE regeneration is effected by a population of injury-activated resident RPE cells that proliferate upon injury and regenerate lost RPE tissue. Understanding how injury-responsive RPE cells proliferate in vivo and the signals/pathways active during the injury response holds significant promise to identify strategies to stimulate or reactivate this ability in the human eye, which would be transformational for treating AMD and other diseases that affect the RPE.
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Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration
Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration
Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration
  • 批准号:
    10646447
  • 项目类别:
  • 资助金额:
    $31.62万
  • 财政年份:
    2019
  • 负责人:
    Jeffrey Gross
  • 依托单位:
DNA Methylation and Hydroxymethylation During Retinal Development and Stem Cell Maintenance
国内基金
海外基金
Kidney injury molecular(KIM-1)介导肾小管上皮细胞自噬在糖尿病肾病肾间质纤维化中的作用
  • 批准号:
    81300605
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    23.0万元
  • 批准年份:
    2013
  • 负责人:
    唐琳
  • 依托单位:
Molecular Plant
Molecular Interaction Reconstruction of Rheumatoid Arthritis Therapies Using Clinical Data
Molecular Plant