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HIGH MOLECULAR WEIGHT TRANSFORMING GROWTH FACTOR BETA

高分子量转化生长因子 Beta

基本信息

批准号：
3195404
负责人：
SAMUEL R NEWCOM
金额：
$ 15.29万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-04-01 至 1993-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3195404
关键词：
Hodgkin's disease biomarker cellular oncology enzyme linked immunosorbent assay epitope mapping histopathology human subject in situ hybridization leukocyte activation disorder molecular cloning molecular weight monoclonal antibody neoplasm /cancer genetics neoplastic cell platelets protein sequence transforming growth factors western blottings

项目摘要

Transforming Growth Factor (TGF) beta has been shown to have a potentially important role in such areas as fetal development, bone repair, wound healing, lymphocyte growth regulation and tumor biology. To date activation of this growth factor has required in vitro acidification (pH 1- 2), an event incompatible with normal physiology. It has recently been demonstrated that Reed-Sternberg cells from Hodgkin's disease secrete TGFbeta active at physiologic pH. This Hodgkin's TGF has a high molecular weight (350,000) as compared to TGFbeta (25,000) but cross-reacts with anti-TGFbeta, competes for TGFbeta cell membrane receptors and is associated with cellular expression of mRNA for TGFbeta. The biological activity of Hodgkin's TGF is similar to that of TGFbeta but is markedly reduced by acidification (97%) and destroyed by exogenous and endogenous proteases. Acidification or exposure to detergents releases the immunoreactive 25,000 dalton TGFbeta peptide with markedly reduced, but measurable biological activity. It is proposed to study the production of a similar high molecular weight form of TGFbeta by other Reed-Sternberg cells including long term and primary Reed-Sternberg cell cultures. Lymph nodes replaced by Hodgkin's disease will be extracted to determine the presence of high molecular weight TGFbeta. Antibodies will be studied which react with platelet TGFbeta and Hodgkin's TGF in ELISA, Western blotting, and histological localization. Monoclonal antibodies will be reviewed to identify those specifically active against epitopes on Hodgkin's TGF and not reactive with platelet TGFbeta. The amino acid sequence of several Hodgkin's TGFs will be determined and compared to the N-terminal sequence of platelet TGFbeta. Using a previously tested cDNA probe for TGFbeta mRNA, in situ hybridization will be used to study tissues involved by Hodgkin's disease and controls. The results of these studies may indicate the discovery of a unique or characteristic form of TGFbeta secreted by Reed-Sternberg cells which provides an important marker for this elusive cell. This finding 1) might permit unequivocal evidence for the Reed-Sternberg cell origin of various Hodgkin's cell lines, and 2) might ultimately lead the way to greater understanding of the biology of the Reed-Sternberg cell and it's presumed central role in Hodgkin's disease.

转化生长因子（TGF）β已被证明具有潜在的在胎儿发育、骨修复、创伤愈合，淋巴细胞生长调节和肿瘤生物学。迄今这种生长因子的活化需要体外酸化（pH 1- 10）。 2），与正常生理不相容的事件。最近有人表明霍奇金病的Reed-Sternberg细胞分泌 TGF β在生理pH下有活性。这种霍奇金TGF β具有高分子量与TGF β（25，000）相比，体重（350，000），但与抗TGF β，竞争TGF β细胞膜受体，与TGF β mRNA的细胞表达相关。生物霍奇金病TGF β的活性与TGF β相似，但明显高于霍奇金病。减少酸化（97%）和破坏的外源性和内源性蛋白酶酸化或接触清洁剂会释放出免疫反应性25，000道尔顿TGF β肽显著降低，但可测量的生物活性。建议研究生产一种类似的高分子量形式的TGF β由其他里德-斯滕伯格细胞，包括长期和原代Reed-Sternberg细胞培养物。淋巴将提取被霍奇金病取代的淋巴结，以确定存在高分子量TGF β。将研究抗体其在ELISA、Western blot和免疫组织化学中与血小板TGF β和霍奇金TGF β反应。印迹和组织学定位。单克隆抗体将是审查以确定那些对表位具有特异性活性的何杰金氏转化生长因子和不与血小板转化生长因子β反应。的氨基酸将测定几种霍奇金TGF的序列并与血小板TGF β的N-末端序列。使用之前测试过的cDNA TGF β mRNA探针，原位杂交将用于研究组织何杰金氏病和疾病控制这些研究的结果可能表明发现了TGF β的独特或特征形式由Reed-Sternberg细胞分泌，其提供了一种重要的标记物，这个难以捉摸的细胞这一发现（1）可以提供明确的证据，各种霍奇金细胞系的Reed-Sternberg细胞起源，以及2）可能最终会引导我们更好地理解 Reed-Sternberg细胞及其在霍奇金淋巴瘤中的核心作用疾病