Wnt responsive stem cells in the prostate

前列腺中的 Wnt 反应性干细胞

• 批准号: 9231705
• 负责人: ZIJIE SUN
• 金额: $ 38.25万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231705
• 关键词: Address; Adult; Androgens; Benign Prostatic Hypertrophy; Biological; Biological Process; Biology; Birth; Bladder; Cells; Complex; Data; Development; Disease; Dorsal; Duct (organ) structure; Ejaculation; Embryo; Embryonic Development; Endocrine Glands; Genes; Genetic; Growth; Growth and Development function; Healthcare Systems; Human; In Vitro; Knowledge; Label; Lead; Maintenance; Malignant Neoplasms; Mediating; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Natural regeneration; Neck; Organogenesis; Pathology; Pathway interactions; Pattern; Perinatal; Play; Property; Prostate; Puberty; Research; Role; Series; Signal Pathway; Signal Transduction; Staging; Stem cells; Testing; Tissues; Urethra; Urogenital Sinus; aging population; base; beta catenin; deprivation; human disease; in vivo; innovation; male; mouse model; novel; pluripotency; postnatal; prostate lateral lobe; prostatitis; public health relevance; reproductive; reproductive organ; response; self-renewal; stem; tissue repair

 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.

 描述（由适用提供）：前列腺是男性的辅助生殖内分泌器官，在射精过程中驱除尿道中的蛋白水解溶液。在人类中，前列腺位于尿道颈部颈部区域周围的膀胱底下的正下方，与许多人类疾病有关，包括良性前列腺增生性增生（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对我们当前的医疗保健系统造成了重大燃烧，并且由于人口老龄化的迅速增长，在未来几十年中，我们的国家将变得更大。尽管过去几十年来进行了激烈的研究工作，但这些疾病的分子机制仍然很少了解。新兴证据表明，需要干细胞在整个生命周期中维护和修复尖端。最近的研究还表明，某些泌尿生殖器窦细胞具有生物学特性，以在前列腺发育的胚胎阶段致力于前列腺命运。 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“规范”或“非规范”途径激活不同的细胞内靶标。规范信号通路主要通过ß-catenin介导。 Wnt/ß-catenin信号通路已被证明在围产期的前列腺发育中至关重要。在前列腺的早期发育中已经确定了Wnt/ß-catenin和雄激素信号通路之间的遗传相互作用。 Axin2是β-catenin的直接转录靶标，在激活Wnt信号后会进行更新。最近的研究表明，AXIN2阳性细胞在多种小鼠组织中具有茎/祖细胞的特性。在此新的R01应用中，我们将使用新型的小鼠模型和其他“最先进的”实验方法来识别前列腺中的Wnt/ß-catenin响应型茎/祖细胞，该细胞从未在现场进行研究。这里提出了三个特定的目的来检验我们的中心假设：Wnt/ß-catenin信号通过其下游反应性细胞在前列腺发育和再生中起着至关重要的作用，并且前列腺中这些反应性细胞的异常激活直接有助于前列腺病理学。拟议的研究旨在获取有关前列腺干/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。