NGF Receptor Regulation of Prostate Growth

描述（由申请人提供）：神经营养因子受体p75 NTR结合生长因子的神经营养因子家族（如NGF）。p75 NTR是肿瘤坏死因子受体超家族的一员。该超家族的特定成员，包括p75 NTR，具有类似的序列基序，称为“死亡结构域”，该结构域指示凋亡功能的启动和生长的抑制。p75 NTR蛋白表达与人类前列腺恶性进展呈负相关。此外，我们已经证明p75 NTR在人类前列腺癌中是一种新的肿瘤抑制因子。这是重要的，因为p75 NTR肿瘤抑制因子的病理消除促进了人类前列腺恶性进展过程中的生长。为了进一步阐明p75 NTR作为前列腺肿瘤抑制因子的作用，我们将验证前列腺癌细胞中功能性p75 NTR修饰受体后效应物从而恢复生长控制抑制的假设。p75 NTR介导的前列腺生长抑制的作用机制将在以下五个具体目标中进行评估。在目标1中，我们将通过NF-kappaB/I-kappaB途径和/或JNK途径的激活来研究p75 NTR介导的死亡受体信号转导，因为它与抑制增殖和激活凋亡有关。在目标2中，我们将通过阻碍细胞周期的进展和改变细胞周期蛋白/cdk全酶复合物的表达/活性来证明p75 NTR依赖性前列腺肿瘤细胞生长的抑制作用。在目标3中，我们将研究p75 wrR介导的凋亡诱导，因为它与促凋亡（如Bax）和抗凋亡（如Bcl-xL）效应物的表达变化以及下游caspase级联的激活有关。在目标4中，我们将研究p75 NTR作为转移抑制因子的双重作用，并在转移性前列腺肿瘤细胞中建立p75 NTR依赖的转移抑制与诱导凋亡和/或减少细胞增殖之间的机制关系。在目标5中，我们将展示p75 NTR载体在SCID小鼠肿瘤内注射的临床前基因治疗应用。这些研究将阐明p75 NTR作为人类前列腺肿瘤和转移抑制因子的作用机制，以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.