CSF-1, CSF-1R AND HUMAN OVARIAN CARCINOMAS

基于在我们目前的NIH奖项的主持下所做的观察 (该申请以竞争性续期形式提交)，我们 我提出了几个新的假设来推动这项研究 包含在此应用程序和其他几个非重叠的 提交给NIH和其他资助机构的申请，这些机构的审查 目前处于待定状态。具体地说，我们的观察使我们 假设： 卵巢癌、子宫内膜癌和乳腺癌的表达水平非常低。 野生型CSF-1R转录本和蛋白质相似--如果不完全相同--到 在巨噬细胞、滋养层细胞和乳腺癌细胞中表达， 而卵巢癌也表达明显更高水平的 新的CSF-1R样转录本和蛋白质可能由 转录和选择性剪接或来自突变或重排 野生型CSF-1R或其他基因组序列。 为了研究这一假设，我们提出： 为了充分鉴定卵巢癌CSF-1R样转录本， 特别强调我们拥有的不寻常的CSF-1R转录本亚型 最近在几个卵巢癌株中观察到。 为了确定这些新的类似CSF-1R的mRNAs是否来自于 被转录的是突变或重新排列的，或者它们是否是新奇的 另一种剪接--野生型CSF-1R基因的产物。 确定新的CSF-1R样蛋白编码的蛋白质异构体 并定义它们的生化和生理功能 与野生型CSF-1R蛋白相关。 为了确定这些新的CSF-1R样转录本的表达和 它们在体内编码的蛋白质相对于良性的野生型CSF-1R 与卵巢上皮肿瘤细胞及预后的关系 其相对野生型CSF-1R表达的意义 应用原位杂交和免疫组织化学技术。 后者将需要开发多克隆抗体和单抗。 识别新型脑脊液-1R受体样蛋白的试剂 与野生型和其他区别激活的酪氨酸的 自身(酪氨酸)磷酸化(新的和野生型)CSF-1RS来自 静止的分子。

Based upon observations made under the auspices of our current NIH award (for which the application is submitted as a competitive renewal), we have formulated several new hypotheses which motivate the research contained in this application and in several other non-overlapping applications submitted to the NIH and other funding agencies whose review is currently pending. Specifically, our observations have led us to hypothesize that: Ovarian, endometrial, and breast carcinomas express very low levels of wild-type CSF-1R transcript and protein similar --if not identical -- to that expressed in macrophages, trophoblast and breast carcinoma cells, while ovarian carcinomas also express significantly higher levels of novel CSF-1R-like transcripts and proteins which may result from transcription and alternative splicing or from mutation or rearrangement of wild-type CSF-1R or other genomic sequences. To investigate this hypothesis, we propose: To fully characterize ovarian carcinoma CSF-1R-like transcripts, with special emphasis on the unusual CSF-1R transcript isoforms which we have recently observed in several ovarian carcinoma lines. To determine whether the locus from which these novel CSF-1R-like mRNAs are transcribed are mutated or rearranged, or whether they are novel alternative splice-products of an otherwise wild-type CSF-1R gene. To define the protein isoforms encoded by the novel CSF-1R-like transcripts and define how their biochemical and physiological functions relate to those of the wild-type CSF-1R protein. To define the expression of these novel CSF-1R-like transcripts and the proteins they encode in vivo relative to the wild-type CSF-1R in benign and neoplastic ovarian epithelial cell as well as the prognostic significance of their expression relative to the wild-type CSF-1R by the application of ISH and immunohistochemical techniques. The latter will require the development of poly- and monoclonal antibody reagents which can discriminate the novel CSF-1R receptor-like proteins from the wild-type and others which discriminate activated, tyrosine auto(tyrosine) phosphorylated (novel and wild-type) CSF-1Rs from the resting molecules.