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

项目总结 早产(PTB)，或在怀孕37周前出生，是导致婴儿死亡的第二大原因 2017年的美国。每年，超过260亿美元用于治疗和护理早产婴儿，而不是 考虑到发展和认知障碍的终生影响。今年早些时候，FDA 发布建议合成孕酮17-羟基孕酮己酸酯(OHPC，Makena®)， 唯一被批准用于预防肺结核的产品，因缺乏临床疗效而退出市场 所需的上市后研究。预防肺结核的新的和创新的治疗选择是绝望的 需要，但肺结核的病因很复杂，有可能在 怀孕是有限的。我们最近开发了一种适合于炎症性肺结核的小鼠模型，并 独特的基于纳米药物的方法，可更有效地通过阴道给生殖器提供治疗药物 一条小路。这些新工具共同导致了早期宫内疾病的治疗性预防的第一次展示。 炎症诱导的肺结核，导致足月产仔，幼崽存活率高， 神经典型的运动发育。通过纳米制剂传递的治疗药物是组蛋白脱乙酰酶。 抑制剂(HDACi)，加或不加外源性黄体酮(P4)。HDACi预防 组蛋白的脱乙酰化，导致更多转录活性的染色质，从而导致基因变化 表情。我们还观察到，P4/HDACi组合抑制了人子宫肌层细胞的收缩和 导致P4受体(PR)异构体B(PR-B)与P4受体异构体A(PR-A)的比率增加， 它被认为可以保持子宫静止和宫颈功能。这支持了HDACi- 诱导的过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 基因表达谱以预防肺结核的方式。这项提案的首要目标是 确定PR-B在预防炎症诱导的肺结核中的作用，以定位 具体到治疗，并评估表观遗传变化是否足以重置 子宫环境有利于胎儿正常发育。如果这些临床前研究成功，我们将产生 结核病表观遗传调控的基本机制知识，以及识别新的细胞途径 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synthetic progestin 17-hydroxyprogesterone caproate (OHPC, Makena®), the only approved product for PTB prevention, be withdrawn from the market due to lack of clinical benefit in a required post-market study.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.