CSF1, CSF1R AND HUMAN OVARIAN CARCINOMAS

根据我们目前的NIH奖赞助下所做的观察， (for申请作为竞争性续期提交），我们 我提出了几个新的假设， 包含在本申请和其他几个非重叠的 提交给NIH和其他资助机构的申请， 目前尚待决定。 具体来说，我们的观察使我们 假设： 卵巢癌、子宫内膜癌和乳腺癌表达极低水平的 野生型CSF-1 R转录物和蛋白质类似-如果不相同- 在巨噬细胞、滋养层细胞和乳腺癌细胞中表达， 而卵巢癌也表达显著更高水平的 新的CSF-1 R样转录物和蛋白质， 转录和可变剪接或突变或重排 野生型CSF-1 R或其它基因组序列。 为了研究这个假设，我们提出： 为了充分表征卵巢癌CSF-1 R样转录物， 特别强调我们所拥有的不寻常的CSF-1 R转录异构体， 最近在几种卵巢癌细胞系中观察到。 为了确定这些新的CSF-1 R样mRNA的基因座是否 是突变还是重排，或者它们是否是新的， 另外的野生型CSF-1 R基因的替代剪接产物。 为了确定由新的CSF-1 R样蛋白编码的蛋白质亚型， 转录本，并定义其生物化学和生理功能 与野生型CSF-1 R蛋白的那些相关。 为了确定这些新的CSF-1 R样转录物的表达， 它们在体内编码的蛋白质相对于良性肿瘤中的野生型CSF-1 R， 与卵巢上皮性肿瘤细胞的关系以及卵巢上皮性肿瘤的预后 它们的表达相对于野生型CSF-1 R的显著性， ISH和免疫组织化学技术的应用。 后者将需要多克隆抗体和单克隆抗体的发展 可区分新的CSF-1 R受体样蛋白的试剂 从野生型和其他歧视激活，酪氨酸 自体（酪氨酸）磷酸化（新的和野生型）CSF-1 R， 静止分子

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.