Wnt responsive stem cells in the prostate

 描述(申请人提供)：前列腺癌是男性的一个附属生殖内分泌器官，在射精时会在尿路中排出蛋白水解液。在人类，前列腺位于膀胱基底部下方，环绕着尿道颈，与许多人类疾病有关，包括良性前列腺增生症(BPH)、前列腺炎和恶性肿瘤。这些疾病和相关并发症的高发病率是我们当前医疗体系的重大负担，而且由于老龄化人口的迅速增加，在未来几十年里，对我们的国家来说，这一负担将变得更加严重。尽管在过去的几十年里已经做出了密集的研究努力，但这些疾病背后的分子机制仍然知之甚少。新出现的证据表明，干细胞在人的一生中需要维持和修复组织。最近的研究还表明，在前列腺发育的胚胎阶段，某些泌尿生殖窦细胞具有决定前列腺细胞命运的生物学特性。Wnt信号通路在发育、形态发生和器官发生中起着关键作用。WNT生长因子通过“典型”或“非典型”途径激活不同的细胞内靶点。典型的信号转导途径主要是通过？连环蛋白介导的。Wnt/？-catenin信号通路在围产期前列腺的发育过程中起着关键作用。在前列腺癌的早期发育过程中，已经发现Wnt/？-catenin和雄激素信号通路之间的遗传相互作用。Axin2是ç-catenin的直接转录靶点，在Wnt信号被激活后上调。最近的研究表明，Axin2阳性细胞在小鼠的各种组织中具有干/祖细胞特性。在这个新的R01应用中，我们将使用新的小鼠模型和其他最先进的实验方法来识别前列腺中从未被研究过的Wnt/？catenin反应性干/祖细胞。这里提出了三个特定的目标来验证我们的中心假说：WNT/？-catenin信号通过其下游反应细胞在前列腺发育和再生中发挥重要作用，以及这些反应细胞在前列腺中的异常激活直接参与了前列腺病理。这项拟议的研究旨在获得有关前列腺干细胞/祖细胞的创新信息，并可能导致对当前范式的新方向和挑战。

 DESCRIPTION (provided by applicant): The Prostate gland is an accessory reproductive endocrine organ in males, which expels proteolytic solution in the urethra during ejaculation. In humans, the prostate is located immediately below the base of the bladder surrounding the neck region of the urethra, and is associated with many human diseases, including benign prostate hyperplasia (BPH), prostatitis, and malignancies. The high morbidity of these disorders and related complications are a significant burden on our current healthcare system, and will become even greater for our nation in the coming decades due to a rapid increase of the aging population. Despite the intense research efforts that have been made in past decades, the molecular mechanisms underlying these disorders are still poorly understood. Emerging evidence has shown that stem cells are required to maintain and repair tissues throughout ones' lifetime. Recent studies also demonstrate that certain urogenital sinus cells carry out biological properties to commit to prostate cell fate at the embryonic stage of prostate development. The Wnt signaling pathway plays a critical role in development, morphogenesis, and organogenesis. Wnt growth factors activate different intracellular targets through either the "canonical" or the "non-canonical" pathways. The canonical signaling pathways are mainly mediated through ß-catenin. The Wnt/ß-catenin signaling pathway has been shown to be critical in the development of the prostate at the perinatal stage. Genetic interactions between Wnt/ß-catenin and androgen signaling pathways have been identified in the early development of the prostate. Axin2 is a direct transcriptional target of ß-catenin and is upregulated after activation of Wnt signaling. Recent studies have shown that Axin2 positive cells have stem/progenitor cell properties in a variety of mouse tissues. In this new R01 application, we will use the novel mouse models and other "state-of-the-art" experimental approaches to identify the Wnt/ß-catenin responsive stem/progenitor cells in the prostate, which has never been investigated in the field. Three specific aims are proposed here to test our central hypothesis: Wnt/ß-catenin signaling plays a essential role in prostate development and regeneration through its downstream responsive cells, and that aberrant activation of these responsive cells in the prostate directly contribute t prostate pathology. The proposed study seeks to gain innovative information on prostatic stem/progenitor cells, and may lead to new directions and challenges to current paradigms.