AIRWAY MYOCYTE PROLIFERATION & LYSOSOMAL HYDROLASE

气道心肌细胞增殖

基本信息

项目摘要

Smooth muscle hyperplasia/hypertrophy is a well recognized pathological change of asthma and may play an important role in the development of airway hyperreactivity, the hallmark of asthma. Lysosomal hydrolases, secretory products of inflammatory cells, are implicated in pathogenesis of allergen-induced asthma and ozone-induced muscarinic hyperreactivity. The proposed study is based on our preliminary findings of a potent mitogenic action of purified lysosomal hydrolases (hexosaminidases) on bovine tracheal airway myocyte by lysosomal hydrolases. The objective of this proposal is to investigate the mechanism(s) involved in airway myocyte proliferation induced by lysosomal hydrolases. Specific aims are 1) To determine if a receptor-ligand interaction (specifically mannose receptor) is required for the mitogenic action of hydrolases. 2) To investigate whether arachidonic acid metabolites, particularly prostaglandin E2 (PGE2) is a mediator of lysosomal hydrolase induced mitogenesis. 3) To investigate whether or not mitogenic action of hydrolases is mediated through the activation of adenylate cyclase. 4) To explore a possible contribution of protein kinase C (PKC) and diacylglycerol (DAG) in the mitogenic effects of lysosomal hydrolases. 5) To establish the role cytosolic calcium in the mitogenic effects of lysosomal hydrolases. To accomplish specific aim 1: a) The presence of mannose receptor on bovine tracheal myocytes will be documented by antibody recognition and receptor type(s) will be characterized. Iodinated glycoproteins will be used for binding study and mannan and fructose-1-phosphate will be used for competition of binding. b) We will examine the effect of blocking receptor-ligand interaction. Receptor inhibitors and blockers will be utilized and their effect will be correlated to 3H-thymidine (TdR) incorporation induced by lysosomal hydrolases. c) Possible internalization of lysosomal hydrolases as a requirement in mitogenic action will be studied. Inhibitors of mannose receptor and agarose and sepharose bound hydrolases will be applied to inhibit internalization. For aims 2, 3, 4, and 5, changes of PGE2 production, cAMP level, DAG level, PKC activity, cytosolic [Ca++] and inositol-triphosphate (IP3) levels; respectively will be studied in the presence and the absence of lysosomal hydrolases. Inhibitors and activators of second messenger systems and cyclooxygenase will be tested for their effects on mitogenesis induced by lysosomal hydrolases. Intracellular cAMP levels and PGE2 production will be measured by RIA and cytosolic calcium will be measured using Fura 2 fluorescent indicator. [32P] ATP, phosphatidyl serine and Histone IIIS will be used to assay PKC activity. Above measurements will be correlated to 3H-TdR incorporation. Understanding the receptor-dependent and the receptor- independent mechanism(s) of lysosomal hydrolase-induced airway myocyte proliferation would allow us to develop a method of prevention of smooth muscle hyperplasia/hypertrophy seen in asthma.
平滑肌增生/肥大是公认的病理性 哮喘的变化,并可能发挥重要作用, 气道高反应性哮喘的标志 溶酶体水解酶, 炎性细胞的分泌产物,参与了 过敏原诱导的哮喘和臭氧诱导的毒蕈碱高反应性。 的 这项研究是基于我们的初步发现, 纯化的溶酶体水解酶(氨基己糖苷酶)对牛 气管气道肌细胞溶酶体水解酶。 的目的 建议研究气道肌细胞参与的机制, 由溶酶体水解酶诱导的增殖。 具体目标是:(1) 确定受体-配体相互作用(特别是甘露糖受体) 是水解酶促有丝分裂作用所必需的。 2)探讨 花生四烯酸代谢物,特别是前列腺素E2(PGE 2) 是溶酶体水解酶诱导的有丝分裂的介质。 3)到 研究水解酶的促有丝分裂作用是否是由 通过腺苷酸环化酶的激活。 4)去探索一种可能的 蛋白激酶C(PKC)和甘油二酯(DAG)在 溶酶体水解酶的促有丝分裂作用。 5)为了建立角色, 溶酶体水解酶促有丝分裂作用中的胞浆钙。 到 实现具体目标1:a)牛血清中甘露糖受体的存在 气管肌细胞将通过抗体识别和受体 类型将被表征。 碘化糖蛋白将用于 结合研究和甘露聚糖和果糖-1-磷酸将用于 竞争约束力。 B)我们将检查阻塞的效果 受体-配体相互作用 受体抑制剂和阻断剂将是 它们的作用将与3 H-胸苷(TdR) 由溶酶体水解酶诱导的掺入。 (c)可能的内在化 溶酶体水解酶作为促有丝分裂作用的必要条件, 研究了 甘露糖受体抑制剂与琼脂糖和琼脂糖结合 将应用水解酶来抑制内化。 对于目标2、3、4, 5. PGE_2产生、cAMP水平、DAG水平、PKC活性、 细胞溶质[Ca++]和肌醇-三磷酸(IP 3)水平;分别将 在存在和不存在溶酶体水解酶的情况下进行研究。 第二信使系统和环氧合酶的抑制剂和激活剂 将测试它们对溶酶体诱导的有丝分裂的影响。 水解酶 将测量细胞内cAMP水平和PGE 2产生 使用Fura 2荧光探针测定细胞内钙离子浓度 指标. [32P]ATP、磷脂酰丝氨酸和组蛋白IIIS将用于 测定PKC活性。 上述测量值将与3 H-TdR相关 合并。 了解受体依赖性和受体- 溶酶体水解酶诱导气道肌细胞的独立机制 扩散将使我们能够开发一种防止平滑 在哮喘中观察到的肌肉增生/肥大。

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 }}

DUKHEE Betty LEW其他文献

DUKHEE Betty LEW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('DUKHEE Betty LEW', 18)}}的其他基金

Mannan, A Potential Therapeutic for Asthma
甘露聚糖,一种治疗哮喘的潜在药物
  • 批准号:
    7591462
  • 财政年份:
    2009
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    6351498
  • 财政年份:
    1998
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    2872945
  • 财政年份:
    1998
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    2468206
  • 财政年份:
    1998
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    6151334
  • 财政年份:
    1998
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION & LYSOSOMAL HYDROLASE
气道心肌细胞增殖
  • 批准号:
    3473615
  • 财政年份:
    1991
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION & LYSOSOMAL HYDROLASE
气道心肌细胞增殖
  • 批准号:
    3473614
  • 财政年份:
    1991
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    2223335
  • 财政年份:
    1991
  • 资助金额:
    $ 10.03万
  • 项目类别:
AIRWAY MYOCYTE PROLIFERATION AND LYSOSOMAL HYDROLASE
气道肌细胞增殖和溶酶体水解酶
  • 批准号:
    2223336
  • 财政年份:
    1991
  • 资助金额:
    $ 10.03万
  • 项目类别:

相似海外基金

Defining new asthma phenotypes using high-dimensional data
使用高维数据定义新的哮喘表型
  • 批准号:
    2901112
  • 财政年份:
    2024
  • 资助金额:
    $ 10.03万
  • 项目类别:
    Studentship
Air pollution and Asthma in Canada: Projections of burden and the value of climate adaptation strategies
加拿大的空气污染和哮喘:负担预测和气候适应战略的价值
  • 批准号:
    485322
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
    Operating Grants
Data-driven model links BMIz to gene expression in pediatric asthma
数据驱动模型将 BMIz 与小儿哮喘基因表达联系起来
  • 批准号:
    493135
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
BIOlogic drug safety and effectiveness interNational pharmacoepidemiologIC study in pregnant women with autoimmune disorders and asthma and their children (BIONIC)
患有自身免疫性疾病和哮喘的孕妇及其子女的生物药物安全性和有效性国际药物流行病学研究(BIONIC)
  • 批准号:
    493526
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
    Operating Grants
Engaging Patient and Caregivers in Using Patient-reported Outcomes Measures in Pediatric Clinical Care for Asthma
让患者和护理人员参与儿科哮喘儿科临床护理中患者报告的结果测量
  • 批准号:
    495593
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
Basophilic oncostatin M fuels nociceptor neuron-induced asthma
嗜碱性制瘤素 M 促进伤害感受器神经元诱发哮喘
  • 批准号:
    485504
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
    Salary Programs
Mechanistic Study of Inspiratory Training in Childhood Asthma
儿童哮喘吸气训练机制研究
  • 批准号:
    10637048
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
Early life exposure to metal mixtures: impacts on asthma and lungdevelopment
生命早期接触金属混合物:对哮喘和肺部发育的影响
  • 批准号:
    10678307
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
Lung resident Treg suppression of Th2 resident memory T cells in allergic asthma
过敏性哮喘中肺常驻 Treg 对 Th2 常驻记忆 T 细胞的抑制
  • 批准号:
    10664599
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
  • 批准号:
    10813753
  • 财政年份:
    2023
  • 资助金额:
    $ 10.03万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了