Botanical derived progestins and their impact on women's health

过去十年来，植物性膳食补充剂的使用量猛增。该市场的一个重要部分 是针对女性的草药补充剂，她们通常用它们来治疗妇科疾病， 这不仅是因为它们具有成本效益优势或可负担性，而且也是因为它们对健康的好处。program是一个 内源性激素和合成孕激素在治疗上用于多种病症 预防子宫增生，增加子宫癌，子宫出血，子宫内膜异位症， 预防早产。选择性孕酮受体（PR）调节剂也用于治疗 预防肌瘤，这发生在80%的妇女。在全国范围内，治疗良性妇科疾病 条件昂贵，每年的费用在130亿至220亿美元之间。因此，研究替代疗法 女性已经在广泛消费的东西是很重要的。然而，一个重大的技术和科学差距 存在：虽然植物被广泛消费，含有相对安全的化合物， 这些化合物尚未被鉴定或进行严格的生物学评价，这是NCCIH的重点领域 （NOT-AT-21-006），其在本申请中特别提出。植物孕激素需要被识别， 研究，以便将其应用于子宫疾病的安全和有效使用。为了解决这一问题，我们的团队 通过鉴定和生物学方法，为化学饮食预防这一新的子领域奠定基础。 来自山茱萸、荆条、红三叶草和丝兰的分子的表征，因为这些含有化合物， 修改PR信号。在目前的提案中，我们的目标是确定其他几种化合物的结构， 通常消费的植物药，修改PR信号，使他们可以检查的安全性和有效性 在临床前化学饮食预防模型中，包括预防纤维瘤、早产和子宫肌瘤， 增生我们的目标是测试我们的假设，即通常消费的植物药用于改善妇女的健康 含有通过三个综合目标调节PR信号传导的化合物。我们将1）分离和表征 通过使用基于细胞的PRE， 荧光素酶测定并测量商业产品中的活性化合物丰度; 2）确认分离的荧光素酶 化合物与受体结合，确定它们是否作为激动剂、拮抗剂或增效剂起作用， 它们修饰脱靶受体，并使用RNA seq改进它们的全基因组转录作用;以及3） 证实使用含植物孕激素的植物性药物进行化学饮食预防可减少早产、子宫 增生或钝化纤维瘤生长。由于对植物生长素含量及其相关的生物学特性知之甚少， 生物活性的植物广泛消费的妇女，这项研究提供了一个深刻的机会， 告知妇科疾病的治疗，并提高消费这些植物的意识 已经.此外，由于妇女已经在食用这些植物，因此应进行研究， 即使存在合成化合物，也要了解它们的胆甾酮改性特性。

Botanical dietary supplement use has skyrocketed over the last ten years. One significant portion of this market is herbal supplements targeted toward women, who commonly use them to treat their gynecological ailments, not only for their cost-effective advantage or affordability, but also for their health benefits. Progesterone is an endogenous hormone and synthetic progestins are used therapeutically for a variety of conditions including prevention of uterine hyperplasia, which increases the risk of uterine cancer, uterine bleeding, endometriosis, and prevention of preterm birth. Selective progesterone receptor (PR) modulators are also used in the treatment of prevention of fibroids, which occur in 80% of women. At a national level, treating benign gynecological conditions is expensive, with an annual cost of between $13–$22 billion. Thus, studying alternative therapies that women are already widely consuming is significant. However, a major technological and scientific gap exists: while botanicals are being widely consumed and contain compounds that are relatively safe, these compounds have not been identified or rigorously biologically evaluated, which is an area of emphasis for NCCIH (NOT-AT-21-006) that is specifically addressed in this application. Phytoprogestins need to be identified and studied in order to apply them for safe and effective use in uterine disorders. To address this, our team laid the groundwork for this new subfield of chemodietary prevention through the identification and biological characterization of molecules from dogwood, vitex, red clover, and yucca, as these contained compounds that modified PR signaling. In the current proposal our goal is to identify the structures of compounds in several other commonly consumed botanicals that modify PR signaling so that they can be examined for safety and efficacy in preclinical chemodietary prevention models, including prevention of fibroids, preterm birth and uterine hyperplasia. We aim to test our hypothesis that commonly consumed botanicals used to improve women’s health contain compounds that regulate PR signaling via three integrated aims. We will 1) Isolate and characterize the structures of phytoprogestin natural products from validated plant material through use of a cell-based PRE- luciferase assays and measure active compound abundance in commercial products; 2) Confirm that isolated compounds bind to a receptor, determine if they function as agonists, antagonists, or potentiators, determine if they modify off-target receptors, and refine their genome-wide transcriptional action using RNA seq; and 3) Confirm that chemodietary prevention using phytoprogestin-containing botanicals reduces preterm birth, uterine hyperplasia or blunts fibroid growth. Since little is known about phytoprogestin content and their associated biological activities from botanicals widely consumed by women, this study presents a profound opportunity to inform the treatment of gynecologic disorders and increase awareness in those consuming these botanicals already. Further, because women are already consuming these botanicals, studies should be conducted to understand their progesterone-modifying properties even if synthetic compounds exist.