AIRWAY MYOCYTE PROLIFERATION & LYSOSOMAL HYDROLASE
气道心肌细胞增殖
基本信息
- 批准号:3473616
- 负责人:
- 金额:$ 10.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1991
- 资助国家:美国
- 起止时间:1991-08-01 至 1996-07-31
- 项目状态:已结题
- 来源:
- 关键词:adenylate cyclase asthma beta N acetylhexosaminidase binding proteins calcium carbohydrate receptor cell differentiation cow cyclic AMP diacylglycerols enzyme inhibitors enzyme mechanism fluorescent dye /probe glycoproteins hyperplasia inhibitor /antagonist mannose mitogens muscle cells prostaglandin E protein kinase C radioimmunoassay radiotracer respiratory hypersensitivity smooth muscle tissue /cell culture trachea
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)
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DUKHEE Betty LEW其他文献
DUKHEE Betty LEW的其他文献
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{{ truncateString('DUKHEE Betty LEW', 18)}}的其他基金
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 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:
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