Endogenous alpha-to-beta cell transdifferentiation in diabetes

糖尿病中的内源性α-β细胞转分化

基本信息

项目摘要

PROJECT SUMMARY AND RELEVANCE An ideal solution to the treatment or cure of diabetes mellitus would be the formation of new functioning β-cells from the patient’s own tissues, thereby avoiding the need for transplant immunosuppression. Abundant recent data has suggested that α-cells are a likely source for endogenous transdifferentiation into β-cells. Here, we describe a pancreatic intraductal viral delivery system in the mouse, where a single infusion of an adeno-associated virus (AAV) carrying a pdx1/mafA expression vector in a diabetic mouse can induce robust and durable α-cell transdifferentiation into β-cells through neogenesis, with recovery of over 60% of the β-cell mass within 4 weeks and persistent, indefinite euglycemia. Serendipitously, when this β-cell neogenesis was induced in NOD mice, the mice became euglycemic for 4 months or more, without any additional therapy or immunosuppression. To our knowledge no clinically applicable β-cell replacement therapy in NOD mice has been successful without immunosuppression. We suspect that the neogenic β-cells may not be rejected because they are “imperfect” β-cells by RNA-seq analysis. Since pancreatic duct injection is routinely performed in humans as a relatively simple, non-surgical procedure, and since numerous viral gene therapy trials are currently ongoing for several diseases, we feel that our approach may be rapidly translatable to humans with diabetes mellitus, potentially both type 1 and type 2. In this proposal we will first better delineate the phenotype of these neogenic mouse β-cells derived from α-cells in terms of function and resistance to stressors that normally can cause β-cell death. We will then strive to better understand how they form, their proliferative capacity, RNA expression and gene methylation profile. We will then study ways to optimize their formation through promoter work for the virus construct, and to better understand ways that anti-AAV neutralizing antibodies may affect the effectiveness of this gene therapy approach. Next, we will pursue the feasibility of a novel lipid nanoparticle technology to replace the need for AAV in the induction of α-to-β-cell transdifferentiation. Since glucagon has been shown to play an important role in α-to-β-cell transdifferentiation, we will study its role in this system. We will study the potential therapeutic effect of such α-to-β-cell transdifferentiation in models of type 2 diabetes mellitus. Lastly, we will investigate the function of human islets that have undergone α-to-β-cell transdifferentiation, both in vitro and in vivo. In summary, we feel that the proposed studies, if successful, should position us well in preparation for clinical trials in humans with diabetes.
项目总结及相关性

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 }}

GEORGE K. GITTES其他文献

GEORGE K. GITTES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('GEORGE K. GITTES', 18)}}的其他基金

Alpha cell conversion to beta cells in non-human primates
非人灵长类动物中α细胞转化为β细胞
  • 批准号:
    10451657
  • 财政年份:
    2018
  • 资助金额:
    $ 37.42万
  • 项目类别:
Alpha cells conversion to beta cells in non-human primates
非人类灵长类动物中的α细胞转化为β细胞
  • 批准号:
    9789262
  • 财政年份:
    2018
  • 资助金额:
    $ 37.42万
  • 项目类别:
Alpha cell conversion to beta cells in non-human primates
非人灵长类动物中α细胞转化为β细胞
  • 批准号:
    10200032
  • 财政年份:
    2018
  • 资助金额:
    $ 37.42万
  • 项目类别:
EGF and TGF-β signaling synergy in β-cell proliferation
EGF 和 TGF-β 信号在 β 细胞增殖中的协同作用
  • 批准号:
    9349505
  • 财政年份:
    2016
  • 资助金额:
    $ 37.42万
  • 项目类别:
Pancreatic Intra-Islet Ducts
胰岛内导管
  • 批准号:
    8626586
  • 财政年份:
    2013
  • 资助金额:
    $ 37.42万
  • 项目类别:
Pancreatic Intra-Islet Ducts
胰岛内导管
  • 批准号:
    8735940
  • 财政年份:
    2013
  • 资助金额:
    $ 37.42万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    8277292
  • 财政年份:
    2009
  • 资助金额:
    $ 37.42万
  • 项目类别:
Smad regulation of pancreatic islet formation
Smad 调节胰岛形成
  • 批准号:
    7632442
  • 财政年份:
    2009
  • 资助金额:
    $ 37.42万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    8080424
  • 财政年份:
    2009
  • 资助金额:
    $ 37.42万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    7905063
  • 财政年份:
    2009
  • 资助金额:
    $ 37.42万
  • 项目类别:

相似海外基金

MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE
小鼠对四氧嘧啶的敏感性机制
  • 批准号:
    6350638
  • 财政年份:
    2001
  • 资助金额:
    $ 37.42万
  • 项目类别:
Körperliches Training und exogene Insulintherapie bei Hunden mit Alloxan-induziertem Diabetes mellitus: Einfluss auf Wechselwirkungen zwischen Endothel und Myokard unter besonderer Berücksichtigung von myokardialem Metabolismus und Apoptoserate
四氧嘧啶诱发糖尿病犬的体能训练和外源性胰岛素治疗:对内皮和心肌之间相互作用的影响,特别是对心肌代谢和细胞凋亡率的影响
  • 批准号:
    5313342
  • 财政年份:
    2001
  • 资助金额:
    $ 37.42万
  • 项目类别:
    Research Fellowships
Possible involvement of facilitated aldose reductase activity in the accelerated vascular remodeling in rabbits with alloxan-induced hyperglycemia
促进醛糖还原酶活性可能参与四氧嘧啶诱导的高血糖兔加速血管重塑
  • 批准号:
    12672209
  • 财政年份:
    2000
  • 资助金额:
    $ 37.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE
小鼠对四氧嘧啶的敏感性机制
  • 批准号:
    6150576
  • 财政年份:
    2000
  • 资助金额:
    $ 37.42万
  • 项目类别:
MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE
小鼠对四氧嘧啶的敏感性机制
  • 批准号:
    2708497
  • 财政年份:
    1999
  • 资助金额:
    $ 37.42万
  • 项目类别:
ALLOXAN RESISTANCE & ISLET REGENERATION IN GUINEA PIG
四氧嘧啶耐药性
  • 批准号:
    3462879
  • 财政年份:
    1989
  • 资助金额:
    $ 37.42万
  • 项目类别:
ALLOXAN RESISTANCE & ISLET REGENERATION
四氧嘧啶耐药性
  • 批准号:
    3462876
  • 财政年份:
    1989
  • 资助金额:
    $ 37.42万
  • 项目类别:
ALLOXAN RESISTANCE & ISLET REGENERATION IN GUINEA PIG
四氧嘧啶耐药性
  • 批准号:
    3462880
  • 财政年份:
    1989
  • 资助金额:
    $ 37.42万
  • 项目类别:
ALLOXAN RESISTANCE & ISLET REGENERATION IN GUINEA PIG
四氧嘧啶耐药性
  • 批准号:
    3462878
  • 财政年份:
    1989
  • 资助金额:
    $ 37.42万
  • 项目类别:
ALLOXAN RESISTANCE & ISLET REGENERATION
四氧嘧啶耐药性
  • 批准号:
    3462877
  • 财政年份:
    1989
  • 资助金额:
    $ 37.42万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了