The Shh-Gli Pathway Regulates Prostate Growth

描述（由申请人提供）：基因Sonic hedgehog（Shh）编码一种分泌的信号肽，在胎儿发育期间作为生长的有效诱导物。分泌的Shh肽与跨膜受体Patched（Ptc）结合并激活hedgehog（Hh）信号转导途径。Hh通路激活通过3个相关Gli转录因子的作用导致基因转录的特异性变化。GN 1和Gli 2协同激活hedgehog（Hh）靶基因的转录，而Gli 3充当转录抑制子。Shh-Gli信号在前列腺生长调节中起着关键作用。它是正常的导管形态发生所必需的，是雄激素诱导的去势前列腺再生长所必需的，最近已被证明可促进前列腺癌的生长和转移。本研究的主要目的是阐明Hh信号调节前列腺生长的分子机制。在上一轮融资中，我们专注于旁分泌信号。我们发现，尿生殖窦（UGS）上皮细胞分泌的Shh激活Hh信号转导通路中的UGS间充质。这诱导间充质靶基因的表达，并激发调节上皮细胞增殖和分化的旁分泌信号传导机制。然而，最近的证据表明，旁分泌信号并不是故事的全部。Shh还激活UGS上皮中的Hh信号转导通路，并且这种自分泌信号传导似乎在调节上皮祖细胞的增殖中发挥特异性和关键性作用。这一建议解决了Hh-Gli信号通过自分泌和旁分泌信号机制的组合调节前列腺生长的新假设。具体来说，我们假设自分泌信号调节上皮祖细胞增殖，而旁分泌信号调节管腔细胞增殖和分化。我们将使用转基因Gli 1和Gli 2突变小鼠和组织重组实验来定量区分前列腺发育中自分泌和旁分泌信号的作用。我们将使用基于细胞的测定来定义调节自分泌和旁分泌信号传导的机制，然后检查异位自分泌和旁分泌信号传导对体内细胞增殖和分化的影响。我们希望表明，分叉的Hh信号自分泌和旁分泌的行动有效地夫妇的祖细胞增殖的调控管腔细胞增殖和分化的控制。这将为我们理解正常生长调节的努力引入一个新的范式，并为Hh信号在前列腺癌中的作用提供重要的见解，其中自分泌和旁分泌信号已被证明促进肿瘤生长。

DESCRIPTION (provided by applicant): The gene Sonic hedgehog (Shh) encodes a secreted signaling peptide that acts as a potent inducer of growth during fetal development. Secreted Shh peptide binds to a transmembrane receptor Patched (Ptc) and activates the hedgehog (Hh) signal transduction pathway. Hh pathway activation results in specific changes in gene transcription through the actions of 3 related Gli transcription factors. GN1 and Gli2 collaborate to activate transcription of hedgehog (Hh) target genes while Gli3 acts as a transcriptional repressor. Shh-Gli signaling plays a pivotal role in prostate growth regulation. It is necessary for normal ductal morphogenesis, is required for androgen-induced re-growth of the castrate prostate, and has recently been shown to promote prostate cancer growth and metastasis. The major goal of our research is to elucidate the molecular mechanisms by which Hh signaling regulates prostate growth. During the previous cycle of funding, we focused on paracrine signaling. We showed that Shh secreted by the urogenital sinus (UGS) epithelium activates the Hh signal transduction pathway in the UGS mesenchyme. This induces expression of mesenchymal target genes and elicits paracrine signaling mechanisms that regulate epithelial proliferation and differentiation. However, recent evidence suggests that paracrine signaling is not the whole story. Shh also activates the Hh signal transduction pathway in the UGS epithelium and this autocrine signaling appears to play a specific and critical role in regulating the proliferation of epithelial progenitor cells. This proposal addresses the novel hypothesis that Hh-Gli signaling regulates prostate growth by a combination of autocrine and paracrine signaling mechanisms. Specifically, we postulate that autocrine signaling regulates epithelial progenitor cell proliferation while paracrine signaling regulates luminal cell proliferation and differentiation. We will use transgenic Gli1 and Gli2 mutant mice and tissue recombination experiments to quantitatively distinguish the actions of autocrine and paracrine signaling in prostate development. We will use cell based assays to define the mechanisms that regulate autocrine and paracrine signaling and then examine the effect of ectopic autocrine and paracrine signaling on cell proliferation and differentiation in vivo. We expect to show that bifurcation of Hh signaling into autocrine and paracrine actions effectively couples control of progenitor cell proliferation to the regulation of luminal cell proliferation and differentiation. This will introduce a novel paradigm into our efforts to understand normal growth regulation and offer important insights into the role of Hh signaling in prostate cancer where both autocrine and paracrine signaling have been shown to promote tumor growth.