NGF Receptor Regulation of Prostate Growth

描述(申请人提供)：神经营养因子受体，p75NTR，结合神经营养因子家族(例如，神经生长因子)。P75NTR是肿瘤坏死因子受体超家族的成员。这个超家族的特定成员，包括p75NTR，具有相似的序列基序，被指定为“死亡结构域”，发出信号启动凋亡功能和抑制生长。P75NTR的蛋白表达与人类前列腺癌的恶性进展呈负相关。此外，我们还发现p75NTR是一种新的前列腺癌肿瘤抑制因子。这一点意义重大，因为在人类前列腺恶性进展过程中，p75NTR肿瘤抑制基因的病理消除有助于促进生长。为了进一步阐明p75NTR在前列腺癌中作为肿瘤抑制因子的作用，我们将测试一种假设，即前列腺癌细胞中具有功能的p75NTR可以修饰受体后效应器，从而重新抑制生长控制。P75NTR介导的抑制前列腺生长的作用机制将在以下五个特定目标中进行评估。在目标1中，我们将研究p75NTR通过核因子-kappaB/I-kappaB途径和/或激活JNK途径介导的死亡受体信号转导，因为它与抑制细胞增殖和激活细胞凋亡有关。在目标2中，我们将通过阻止细胞周期的进展和细胞周期蛋白/cdk全酶复合体的表达/活性的变化来证明p75NTR依赖于抑制前列腺肿瘤细胞的生长。在目标3中，我们将研究p75WRR介导的细胞凋亡诱导，因为它与促凋亡(如Bax)和抗凋亡(如Bclxl)效应因子的表达变化以及下游caspase级联反应的激活有关。在目标4中，我们将研究p75NTR作为转移抑制因子的双重作用，并建立p75NTR依赖的转移抑制与诱导转移性前列腺癌细胞凋亡和/或抑制细胞增殖之间的机制关系。在目的5中，我们将通过瘤内注射的方式展示p75NTR载体在SCID小鼠中的临床前基因治疗应用。这些研究将阐明p75NTR作为肿瘤和转移抑制因子的作用机制(S)及其在前列腺癌基因治疗中的潜在应用。

DESCRIPTION (provided by applicant): The neurotrophin receptor, p75 NTR, binds the neurotrophin family (e.g. NGF) of growth factors. The p75 NTR is a member of the tumor necrosis factor receptor superfamily. Specific members of this superfamily, including the p75 NTR, share similar sequence motifs designated "death domains" that signal initiation of apoptotic function and inhibition of growth. The p75 NTR exhibits an inverse association of protein expression with malignant progression of the human prostate. Furthermore, we have shown that the p75 NTR is a novel tumor suppressor in human prostate cancer. This is significant since the pathologic elimination of the p75 NTR tumor suppressor facilitates growth during malignant progression of the human prostate. To further elucidate the role of the p75 NTR as a tumor suppressor in the prostate we will test the hypothesis that a functional p75 NTR in prostate cancer cells modifies post-receptor effectors that regains inhibition of growth control. The mechanisms of action of p75 NTR mediated suppression of prostate growth will be assessed in the following five specific aims. In aim 1, we will examine p75 NTR mediated death receptor signal transduction via both the NF-kappaB/I-kappaB pathway and/or activation of the JNK pathway as it relates to inhibition of proliferation and activation of apoptosis. In aim 2, we will demonstrate p75 NTR dependent inhibition of prostate tumor cell growth via impeded progression of the cell cycle and changes in expression/activity of the cyclin/cdk holoenzyme complexes. In aim 3, we will examine p75 wrR mediated induction of apoptosis as it relates to changes in the expression ofpro-apoptotic (e.g. Bax) and anti-apoptotic (e.g. Bcl-xL) effectors, and activation of the downstream caspase cascade. In aim 4 we will examine the dual role of p75 NTR as a metastasis suppressor and establish a mechanistic relationship between p75 NTR dependent suppression of metastasis and induction of apoptosis and/or reduced cell proliferation in the metastatic prostate tumor cells. In aim 5, we will demonstrate pre-clinical gene therapy application of p75 NTR vectors by intra-tumoral injection in SCID mice. These studies should elucidate the mechanism(s) of action of the p75 NTR as a tumor and metastasis suppressor of human prostate growth, and its potential application for gene therapy of prostate cancer.