ABCB5-positive stem cells for LSCD therapy

用于 LSCD 治疗的 ABCB5 阳性干细胞

基本信息

  • 批准号:
    9457457
  • 负责人:
  • 金额:
    $ 48.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Many mammalian organs (skin, stomach, intestines, colon, and eye) possess a source of adult stem cells that continually replenishes their rapidly self-renewing epithelial surface. One important challenge in regenerative medicine is replacing these stem cells when they are eliminated following an injury or disease. The eye contains two highly specialized stratified squamous epithelia- the conjunctival epithelium and the corneal epithelium. A healthy corneal epithelium is essential for maintaining a clear cornea and normal vision. The limbus contains a small subpopulation of rare limbal stem cells (LSC) that continually repopulates the corneal epithelium. Patients with limbal stem cell deficiency (LSCD) are unable to regenerate the corneal epithelium, resulting in "conjunctivalization" of the corneal stroma that triggers neovascularization, chronic inflammation, and ultimately blindness due to an irreversibly opaque cornea. Several approaches have been used to replace LSC by transplanting limbal tissue or ex vivo expanded limbal cells. These procedures have obtained some success, mainly using autologous limbal tissue from patients with unilateral LSCD. Patients with bilateral LSCD have no source of autologous LSC and much less success was observed with allogeneic limbal tissue transplants. However, success of all these procedures was severely limited by the inability to prospectively identify and purify LSC. This problem was recently addressed by a new collaborative research group from the departments of: Ophthalmology, Genetics, and Transplantation Research (Mass Eye & Ear, Brigham & Women's Hospital and Boston Children's Hospital) that comprises the three PIs of this proposal, who discovered that the ABCB5 gene, a new member of the ATP-binding cassette (ABC) superfamily of active transporters, is expressed by stem cells of the limbus in both mouse and human tissues. Normal function of ABCB5+ LSC is required for corneal development and repair, through critical roles in stem cell maintenance and survival, and knockout mice that lack ABCB5 do not develop a fully differentiated mature corneal epithelium. Importantly, ABCB5 is a cell surface protein and specific monoclonal antibodies developed by the laboratories of Co-PIs Drs. M. Frank and N. Frank are capable of isolating pure ABCB5-positive cells from the limbus. Transplantation of purified human ABCB5+ (but not ABCB5-) LSC onto the corneal stroma of immunodeficient mice with induced LSCD restored the corneal epithelium, indicating that this purified LSC population has the potential to significantly improve therapy for corneal disease associated with LSCD. The current application builds upon these results to address the important challenges that prevent successful stem cell therapy for patients with unilateral or bilateral LSCD. Our overall hypothesis is that ABCB5+ stem cells from the limbus can be isolated and expanded ex vivo as a source of stem cells to regenerate the corneal epithelium when transplanted to recipients with either a unilateral or bilateral LSCD.
 描述(由申请人提供):许多哺乳动物器官(皮肤、胃、肠、结肠和眼睛)都具有成体干细胞来源,这些干细胞不断地覆盖其快速自我更新的上皮表面。再生医学的一个重要挑战是在损伤或疾病后消除这些干细胞时替换它们。眼睛包含两个高度特化的复层鳞状上皮-结膜上皮和角膜上皮。健康的角膜上皮对于维持透明的角膜和正常的视力至关重要。利姆布斯含有一小部分稀有的角膜缘干细胞(LSC)亚群,这些细胞不断地重新增殖角膜上皮。患有角膜缘干细胞缺乏症(LSCD)的患者不能再生角膜上皮,导致角膜基质的“结膜化”,其触发新血管形成、慢性炎症,并且最终由于不可逆的不透明角膜而失明。已经使用了几种方法通过移植角膜缘组织或离体扩增的角膜缘细胞来替代LSC。这些手术已经取得了一定的成功,主要是使用来自单侧LSCD患者的自体角膜缘组织。双侧LSCD患者没有自体LSC来源,同种异体角膜缘组织移植的成功率要低得多。然而,所有这些方法的成功都受到无法前瞻性地鉴定和纯化LSC的严重限制。这个问题最近由来自以下部门的一个新的合作研究小组解决:眼科学、遗传学和移植研究(Mass Eye & Ear,Brigham & Women's Hospital和Boston Children's Hospital),包括该提案的三位PI,他们发现ABCB 5基因,一个ATP结合盒(ABC)主动转运蛋白超家族的新成员,在小鼠和人的组织中由利姆布斯的干细胞表达。通过在干细胞维持和存活中的关键作用,ABCB 5 + LSC的正常功能是角膜发育和修复所需的,并且缺乏ABCB 5的敲除小鼠不能发育完全分化的成熟角膜上皮。重要的是,ABCB 5是一种细胞表面蛋白和特异性单克隆抗体,由Co-PI博士的实验室开发。弗兰克和N. Frank能够从利姆布斯分离出纯的ABCB 5阳性细胞。将纯化的人ABCB 5+(但不是ABCB 5-)LSC移植到具有诱导的LSCD的免疫缺陷小鼠的角膜基质上恢复了角膜上皮,表明该纯化的LSC群体具有显著改善与LSCD相关的角膜疾病的治疗的潜力。目前的应用建立在这些结果的基础上,以解决阻碍单侧或双侧LSCD患者成功进行干细胞治疗的重要挑战。我们的总体假设是,来自利姆布斯的ABCB 5+干细胞可以作为干细胞来源离体分离和扩增,以在移植到患有单侧或双侧LSCD的受体时再生角膜上皮。

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 }}

NATASHA Y FRANK其他文献

NATASHA Y FRANK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 }}

{{ truncateString('NATASHA Y FRANK', 18)}}的其他基金

Targeting therapeutic resistance in glioblastoma
靶向胶质母细胞瘤的治疗耐药性
  • 批准号:
    10588313
  • 财政年份:
    2023
  • 资助金额:
    $ 48.95万
  • 项目类别:
Skin-Intrinsic Immunosuppressive Mesenchymal Stem Cells and aGVHD
皮肤固有免疫抑制间充质干细胞和 aGVHD
  • 批准号:
    10345441
  • 财政年份:
    2022
  • 资助金额:
    $ 48.95万
  • 项目类别:
Skin-Intrinsic Immunosuppressive Mesenchymal Stem Cells and aGVHD
皮肤固有免疫抑制间充质干细胞和 aGVHD
  • 批准号:
    10545022
  • 财政年份:
    2022
  • 资助金额:
    $ 48.95万
  • 项目类别:
Multipotent ABCB5-positive cell therapeutics for corneal disease
用于治疗角膜疾病的多能 ABCB5 阳性细胞疗法
  • 批准号:
    9884771
  • 财政年份:
    2018
  • 资助金额:
    $ 48.95万
  • 项目类别:
Multipotent ABCB5-positive cell therapeutics for corneal disease
用于治疗角膜疾病的多能 ABCB5 阳性细胞疗法
  • 批准号:
    10374830
  • 财政年份:
    2018
  • 资助金额:
    $ 48.95万
  • 项目类别:
Multipotent ABCB5-positive cell therapeutics for corneal disease
用于治疗角膜疾病的多能 ABCB5 阳性细胞疗法
  • 批准号:
    10133082
  • 财政年份:
    2018
  • 资助金额:
    $ 48.95万
  • 项目类别:
ABCB5-positive stem cells for LSCD therapy
用于 LSCD 治疗的 ABCB5 阳性干细胞
  • 批准号:
    10668673
  • 财政年份:
    2016
  • 资助金额:
    $ 48.95万
  • 项目类别:
ABCB5-positive stem cells for LSCD therapy
用于 LSCD 治疗的 ABCB5 阳性干细胞
  • 批准号:
    9895803
  • 财政年份:
    2016
  • 资助金额:
    $ 48.95万
  • 项目类别:
ABCB5-positive stem cells for LSCD therapy
用于 LSCD 治疗的 ABCB5 阳性干细胞
  • 批准号:
    9106905
  • 财政年份:
    2016
  • 资助金额:
    $ 48.95万
  • 项目类别:
ABCB5-positive stem cells for LSCD therapy
用于 LSCD 治疗的 ABCB5 阳性干细胞
  • 批准号:
    9316257
  • 财政年份:
    2016
  • 资助金额:
    $ 48.95万
  • 项目类别:

相似海外基金

Understanding the Volatile Evolution of Arc Magmas: Alkalies and Mixed (H2O + CO2) Volatile Solubility in Basalts and Basaltic Andesites
了解弧岩浆的挥发性演化:玄武岩和玄武安山岩中的碱金属和混合 (H2O CO2) 挥发性溶解度
  • 批准号:
    0838563
  • 财政年份:
    2009
  • 资助金额:
    $ 48.95万
  • 项目类别:
    Standard Grant
Clinker's coating:role of alkalies and refractories texture
熟料的涂层:碱和耐火材料质地的作用
  • 批准号:
    200906-1996
  • 财政年份:
    1999
  • 资助金额:
    $ 48.95万
  • 项目类别:
    Collaborative Research and Development Grants
Clinkers coating:role of alkalies and refractories texture
熟料涂层:碱和耐火材料质地的作用
  • 批准号:
    200906-1996
  • 财政年份:
    1998
  • 资助金额:
    $ 48.95万
  • 项目类别:
    Collaborative Research and Development Grants
Clinker's coating:role of alkalies and refractories texture
熟料的涂层:碱和耐火材料质地的作用
  • 批准号:
    200906-1996
  • 财政年份:
    1997
  • 资助金额:
    $ 48.95万
  • 项目类别:
    Collaborative Research and Development Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了