Nanomedicine-based approach for characterizing the epigenome in prevention of inflammation-induced preterm birth.

项目摘要 早产（PTB），或妊娠37周之前出生，是婴儿死亡的第二大原因， 2017年美国。每年，超过260亿美元用于治疗和护理早产儿，而不是 解释发展和认知障碍的终身影响。今年早些时候，FDA 发布了一项建议，即合成的孕酮17-羟孕酮己酸酯（OHPC，Makena®）， 唯一批准用于预防肺结核的产品，由于缺乏临床获益而退出市场， 需要进行上市后研究。预防PTB的新的和创新的治疗选择是绝望的 需要，但PTB的病因是复杂的，组织取样和临床试验的潜力， 怀孕是有限的。我们最近开发了一种适应性炎症诱导的PTB小鼠模型， 独特的基于纳米医学的方法，用于更有效地将治疗剂经阴道递送到生殖系统， 道。总之，这些新的工具导致了第一次证明治疗性预防早期子宫内膜异位症。 炎症诱导的PTB，导致具有高百分比幼仔存活率的窝仔的足月分娩， 神经型运动发育。通过纳米制剂递送的治疗剂是组蛋白脱乙酰酶 抑制剂（HDACi）给药，需要或不需要额外的外源性孕酮（P4）。HDACi预防 组蛋白脱乙酰化，导致更多的转录活性染色质，从而改变基因表达。 表情我们还观察到P4/HDACi组合抑制人子宫肌层细胞收缩性， 导致P4受体（PR）亚型B（PR-B B）与P4受体亚型A（PR-A）相比的比率增加， 其被认为维持子宫静止和宫颈功能。这支持了HDACi- 诱导的超乙酰化为配体结合的PR创造了更有利的染色质结构，以改变 基因表达谱的方式，防止肺结核。本提案的总体目标是 确定PR-B在预防炎症诱导的PTB中的作用，绘制表观遗传变化， 特异于治疗性治疗，并评估表观遗传变化是否足以重置 正常胎儿发育的子宫环境。如果这些临床前研究成功，我们将产生 PTB表观遗传调控的基本机制知识，以及确定新的细胞途径 这可能是预防肺结核的重要目标。

PROJECT SUMMARY Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Earlier this year, the FDA issued a recommendation that the synthetic progestin 17-hydroxyprogesterone caproate (OHPC, Makena®), the only approved product for PTB prevention, be withdrawn from the market due to lack of clinical benefit in a required post-market study. New and innovative therapeutic options for preventing PTB are desperately needed, but the etiology of PTB is complex and the potential for tissue sampling and clinical trials during pregnancy is limited. We recently developed an adapted mouse model of inflammation-induced PTB and a unique nanomedicine-based approach for more efficient vaginal delivery of therapeutics to the reproductive tract. Together, these new tools led to the first demonstration of therapeutic prevention of early intrauterine inflammation-induced PTB that led to full term delivery of litters with high percentages of pup viability and neurotypical motor development. The therapeutics delivered via the nanoformulation were histone deacetylase inhibitors (HDACi) dosed with or without the need for additional exogenous progesterone (P4). HDACi prevent deacetylation of histones, leading to more transcriptionally active chromatin, and thus, changes in gene expression. We also observed that the P4/HDACi combination inhibited human myometrial cell contractility and led to an increase in the ratio of P4 receptor (PR) isoform B (PR-B) compared to P4 receptor isoform A (PR-A), which is thought to maintain uterine quiescence and cervical competence. This supports the idea that HDACi- induced hyperacetylation creates a more favorable chromatin structure for ligand-bound PR to change the gene expression profile in a manner that prevents PTB. The overarching goals of this proposal are to determine the role of PR-B in the prevention of inflammation-induced PTB, to map epigenetic changes that are specific to therapeutic treatment, and to evaluate whether the epigenetic changes are sufficient to reset the uterine environment for normal fetal development. If these preclinical studies are successful, we will generate fundamental mechanistic knowledge of epigenetic regulation in PTB, as well as identify new cellular pathways that may be important targets for PTB prevention.