Wnt responsive stem cells in the prostate

 描述（由申请人提供）：前列腺是男性的辅助生殖内分泌器官，在射精期间在尿道中排出蛋白水解溶液。在人类中，前列腺位于尿道颈部周围膀胱底部的正下方，并且与许多人类疾病相关，包括良性前列腺增生（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保健系统的重大负担，并且由于人口老龄化的快速增加，在未来几十年内对我们国家来说将变得更大。尽管在过去的几十年里进行了大量的研究工作，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，某些尿生殖窦细胞在前列腺发育的胚胎阶段就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关键作用。Wnt生长因子通过“经典”或“非经典”途径激活不同的细胞内靶标。经典信号通路主要通过β-连环蛋白介导。Wnt/β-连环蛋白信号通路已被证明在围产期前列腺的发育中是关键的。Wnt/β-连环蛋白和雄激素信号通路之间的遗传相互作用已在前列腺的早期发育中被确定。Axin 2是β-连环蛋白的直接转录靶标，并且在Wnt信号传导激活后上调。最近的研究表明，Axin 2阳性细胞在多种小鼠组织中具有干/祖细胞特性。在这个新的R 01应用中，我们将使用新的小鼠模型和其他“最先进”的实验方法来鉴定前列腺中的Wnt/β-连环蛋白反应性干/祖细胞，这在该领域从未被研究过。本文提出了三个具体目标来验证我们的中心假设：Wnt/β-连环蛋白信号通过其下游反应细胞在前列腺发育和再生中起重要作用，并且前列腺中这些反应细胞的异常激活直接导致前列腺病理学。这项研究旨在获得前列腺干/祖细胞的创新信息，并可能导致新的方向和挑战目前的范式。

 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.