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（例如NGF）。p75 NTR是肿瘤坏死因子受体超家族的成员。该超家族的特定成员，包括p75 NTR，共享称为“死亡结构域”的类似序列基序，其发出细胞凋亡功能和生长抑制的起始信号。p75 NTR蛋白表达与前列腺恶性进展呈负相关。此外，我们已经表明，p75 NTR是一种新的肿瘤抑制剂在人类前列腺癌。这是重要的，因为p75 NTR肿瘤抑制因子的病理消除促进了人前列腺恶性进展期间的生长。为了进一步阐明p75 NTR在前列腺中作为肿瘤抑制因子的作用，我们将检验以下假设：前列腺癌细胞中的功能性p75 NTR修饰受体后效应物，该受体后效应物重新抑制生长控制。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，我们将研究p75 NTR介导的死亡受体信号转导通过NF-κ B/I-κ B途径和/或JNK途径的激活，因为它涉及增殖的抑制和凋亡的激活。在目标2中，我们将证明p75 NTR依赖性抑制前列腺肿瘤细胞的生长，通过阻碍细胞周期的进展和细胞周期蛋白/cdk全酶复合物的表达/活性的变化。在目标3中，我们将研究p75 wrR介导的凋亡诱导，因为它涉及促凋亡（例如Bax）和抗凋亡（例如Bcl-xL）效应物表达的变化，以及下游caspase级联的激活。在目标4中，我们将研究p75 NTR作为转移抑制剂的双重作用，并建立转移性前列腺肿瘤细胞中p75 NTR依赖性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，我们将通过在SCID小鼠中肿瘤内注射来证明p75 NTR载体的临床前基因治疗应用。这些研究将阐明p75 NTR作为人前列腺生长的肿瘤和转移抑制剂的作用机制，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.