Intracellular Amyloidogenesis and Apoptosis in NIDDM

NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡

基本信息

项目摘要

DESCRIPTION (provided by applicant) Non-insulin dependent diabetes (NIDDM) is an aging-related disease associated with arnyloid formation in the pancreas and loss of beta cell mass. The mechanism(s) of pancreatic beta cell death in NIDDM are unknown. NIDDM is a major disease that currently affects approximately 7.2 million Americans with annual costs exceeding $100 billion. A mutation (IAPPS20G) in he human wild-type islet amyloid precursor protein (hIAPPWT, amylin) has been associated with premature onset NIDDM in Japanese populations, providing a direct linkage of the IAPP gene with the genesis of NIDDM. IAPP is the major component of islet cell amyloid deposits which are a hallmark of NIDDM, suggesting that islet amyloid may be involved in the pathogenesis of this disease. We demonstrated that hIAPPWT expression in COS-1 and betaTC-3 cells results in the accumulation of intracellular amyloid within the endoplasmic reticulum (ER)/Golgi and induction of apoptosis. The expression of IAPPS2OG in these cells results in increased cytotoxicty and this is correlated with its increased in vitro amyloidogenic character as compared to IAPPWT. Accordingly, we have hypothesized that: (i) intracellular amyloidogenesis is a primary cause of beta cell death, and (ii) protective mechanisms that prevent intracellular amyloidogenesis are compromised by factors predisposing to NIDDM. Our preliminary data indicate that the accumulation of amyloid within he ER/Golgi is associated with an early induction of the molecular chaperone Bip/GRP78, a protein that appears to be signalling intermediate for two ER stress response pathways, unfolded protein response (UPR) and ER overload response (EOR), that are involved in ER quality control. Our data suggest that intracellular amyloid accumulation and subsequent induction of apoptosis may be mediated by one or both of these pathways. In the current studies we will: (1) assess the physiologic relevance of IAPPWT and IAPPS20G expression and amyloid formation and their relative ability to lead to diabetes in mouse knock-in models, (2) establish whether the UPR or EOR stress response is activated by intracellular amyloid accumulation and their role(s) in inducing apoptosis, (3) determine whether changes in ER Ca2+ activate apoptosis. (4) Determine the relative role of mitochondrial proteins in amyloid-induced apoptosis, and (5) define the distal caspase mediated pathways leading to apoptosis. These studies will increase our understanding of the contribution of intracellular amyloid accumulation, induction of apoptosis, and/or interference with ER trafficking to the pathogenesis of NIDDM.
描述(由申请人提供)非胰岛素依赖性糖尿病(NIDDM)为 与胰腺中砷形成相关的与衰老有关的疾病 β细胞量的损失。 NIDDM中胰腺β细胞死亡的机制 是未知的。 NIDDM是一种主要疾病,目前影响约7.2 million Americans with annual costs exceeding $100 billion.突变 (iApps20g)在人类野生型胰岛淀粉样蛋白蛋白(hiappwt, 氨基蛋白)与日本人群中的过早发作NIDDM有关, providing a direct linkage of the IAPP gene with the genesis of NIDDM. Iapp是 the major component of islet cell amyloid deposits which are a hallmark of NIDDM,表明胰岛淀粉样蛋白可能与 这种疾病。我们证明了hiappwt在cos-1和betatc-3中的表达 细胞导致细胞内淀粉样蛋白在 内质网(ER)/高尔基体和凋亡的诱导。表达 IAPPS2OG in these cells results in increased cytotoxicty and this is correlated with its increased in vitro amyloidogenic character as compared to IAPPWT. 因此,我们假设:(i)细胞内淀粉样生成是一种 β细胞死亡的主要原因以及(ii)防止的保护机制 细胞内淀粉样生成受到偏爱NIDDM的因素的损害。 Our preliminary data indicate that the accumulation of amyloid within he ER/Golgi与分子伴侣的早期诱导有关 BIP/GRP78,一种蛋白质,似乎是两个ER的信号传导中间 stress response pathways, unfolded protein response (UPR) and ER overload 响应(EOR),与ER质量控制有关。 Our data suggest that 细胞内淀粉样蛋白的积累和随后的凋亡诱导可能是 mediated by one or both of these pathways.在当前的研究中,我们将:(1) 评估IAPPWT和IAPPS20G表达和淀粉样蛋白的生理相关性 形成及其相对能够导致糖尿病的相对能力 模型,(2)确定UPR或EOR应力响应是否被激活 细胞内淀粉样蛋白的积累及其在诱导凋亡中的作用,(3) determine whether changes in ER Ca2+ activate apoptosis. (4)确定 线粒体蛋白在淀粉样蛋白诱导的凋亡中的相对作用,(5) 定义导致凋亡的远端caspase介导的途径。这些研究 将增加我们对细胞内淀粉样蛋白的贡献的理解 积累,诱导凋亡和/或干扰ER运输 NIDDM的发病机理。

项目成果

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数据更新时间:2024-06-01

NORMAN L EBERHARDT的其他基金

Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    6851720
    6851720
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    6621081
    6621081
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    7010672
    7010672
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
INTRACELLULAR AMYLOIDOGENESIS AND APOPTOSIS IN NIDDM
NIDDM 中的细胞内淀粉样生成和细胞凋亡
  • 批准号:
    6039413
    6039413
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
INTRACELLULAR AMYLOIDOGENESIS AND APOPTOSIS IN NIDDM
NIDDM 中的细胞内淀粉样生成和细胞凋亡
  • 批准号:
    6350745
    6350745
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    6702217
    6702217
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
TUMOR SUPPRESSORS AND DIFFERENTIATED THYROID CANCER
肿瘤抑制剂和分化型甲状腺癌
  • 批准号:
    6137717
    6137717
  • 财政年份:
    1999
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
TUMOR SUPPRESSORS AND DIFFERENTIATED THYROID CANCER
肿瘤抑制剂和分化型甲状腺癌
  • 批准号:
    2744468
    2744468
  • 财政年份:
    1999
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Tumor Suppressors and Differentiated Thyroid Cancer
肿瘤抑制剂和分化型甲状腺癌
  • 批准号:
    7248670
    7248670
  • 财政年份:
    1999
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Tumor Suppressors and Differentiated Thyroid Cancer
肿瘤抑制剂和分化型甲状腺癌
  • 批准号:
    7117826
    7117826
  • 财政年份:
    1999
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:

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相似海外基金

Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    6851720
    6851720
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    6621081
    6621081
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
Intracellular Amyloidogenesis and Apoptosis in NIDDM
NIDDM 中的细胞内淀粉样蛋白生成和细胞凋亡
  • 批准号:
    7010672
    7010672
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
INTRACELLULAR AMYLOIDOGENESIS AND APOPTOSIS IN NIDDM
NIDDM 中的细胞内淀粉样生成和细胞凋亡
  • 批准号:
    6039413
    6039413
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别:
INTRACELLULAR AMYLOIDOGENESIS AND APOPTOSIS IN NIDDM
NIDDM 中的细胞内淀粉样生成和细胞凋亡
  • 批准号:
    6350745
    6350745
  • 财政年份:
    2000
  • 资助金额:
    $ 25.03万
    $ 25.03万
  • 项目类别: