Understanding OPA1 mutation-driven dominant optic atrophy using human PSC-derived retinal ganglion cells

使用人 PSC 来源的视网膜神经节细胞了解 OPA1 突变驱动的显性视神经萎缩

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Dominant optic atrophy (DOA) is the most prevalent genetic optic neuropathy, affecting roughly 1:12,000 to 1:50,000 individuals worldwide. DOA patients exhibit retinal ganglion cell (RGC) degeneration, which leads to progressive bilateral vision loss. The majority of DOA cases are caused by mutations in the gene optic atrophy 1 (OPA1), a nuclear gene that encodes a protein targeted to the inner mitochondrial membrane. Interestingly, although OPA1 is ubiquitously expressed in all human tissues, RGCs appear to be the only cell type affected by OPA1 mutations. It is therefore essential to study DOA in human RGCs in order to understand the pathological mechanisms present in these cells that render them particularly prone to degeneration. However, studies of human RGCs have been historically difficult due to the rarity of primary retinal tissues and scarcity of RGCs, which only comprise ~2% of the total retinal cells. This proposal seeks to address the significant unmet need for developing human RGC models of DOA. Advances in stem cell technology have enabled our laboratory to routinely produce human RGCs from human pluripotent stem cell (hPSC)-derived 3D retinal organoid cultures. In addition, I have established OPA1 mutant hPSC lines by using gene editing technology and by reprogramming DOA patients’ peripheral blood cells. Differentiating these OPA1 mutant hPSC lines into retinal organoids will provide the first opportunity to establish DOA disease models in authentic, human RGCs. In the proposed study, I will use OPA1 mutant hPSC-derived human RGC populations to investigate pathological mechanisms of OPA1 mutation-mediated RGC degeneration. As OPA1 plays significant roles in promoting mitochondrial fusion, maintaining the integrity of the cristae, and stabilizing super complexes of the respiratory chain, RGC death observed in DOA patients is likely a result of mitochondrial defects that can lead to an insufficient energy supply, increased oxidative stress, and/or leakage of cytochrome c into the cytoplasm. I will investigate the mitochondrial dynamics, cristae structure, and metabolic state of OPA1-mutant RGCs to delineate whether changes in these fundamental processes underly the RGC degeneration observed in DOA patients. Findings from this study will advance our understanding of the pathological mechanisms affecting DOA patients’ RGCs and facilitate the development of therapies that can preserve or rescue vision in DOA patients. Additionally, our findings could provide important insights into other neurodegenerative diseases that share common metabolic deficiencies with DOA.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Katherine Anne Pohl其他文献

Katherine Anne Pohl的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.6万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了