Lifelong impact of PAE on stem cell dynamics and cellular aging

项目总结： 产前酒精暴露(PAE)很常见，可能导致脑部残疾和发育障碍。这个 PAE的影响不仅处于早期发展阶段，而且还可能导致整个 寿命。这些次要问题可能包括与衰老相关的疾病的发病率更高和发病更早， 包括心血管疾病、自身免疫性疾病，如关节炎和骨密度下降。这个 这些与衰老有关的疾病的早期发病表明，PAE的后果是组织过早衰老 和器官。还有一个尚未得到满足的需求，即更好地了解PAE诱导的过早衰老并确定 可用来延缓或预防这些次级健康状况的潜在机制。 我们知道PAE是一种强大的致畸剂，可以重新编程干细胞。我们的假设是，这种干细胞 重新编程会产生终生后果，包括干细胞的过早衰老是一种 会导致全身老化。这一假说得到了已发表的文献的支持，这些文献表明PAE可以破坏茎干 细胞自我更新，部分原因是过早或异常分化，而这些破坏了干细胞 这种行为会一直持续到成年。基于这些数据，我们计划解决两个问题：第一，PAE在 人类在整个生命周期中会削弱干细胞的功能吗？“；其次，”PAE是否会导致或 会加剧人类干细胞老化吗？“ 为了解决上述两个问题，我们计划创建人诱导多能干细胞(HiPSCs)，作为 这些细胞的早期传代保留了衰老的表观遗传标记。这些单元格将从区域派生 以及不同种族的患有PAE/胎儿酒精的新生儿、儿童/青少年和成人队列 谱系障碍(FASD)和匹配的对照组。在目标1中，我们计划使用一组细胞和 分子分析评估PAE/FASD诱导的干细胞生长、自我更新和三联体的变化 (外胚层、中胚层、内胚层)分化。在目标2中，我们计划评估干细胞老化的变化， 包括衰竭、衰老和促炎分子的释放，作为衰老的一部分- 相关的分泌表型。 我们的首要目标是，最终确定调节继发性肺炎出现的潜在机制。 FASDS患者的健康状况，符合NIAAA的使命(RFA-AA-21-014)。 已知PAE可抑制干细胞功能。然而，组织干细胞也可能成为 预防和治疗PAE引起的早衰。在这些研究结束后，我们将会有： 首先，创建了一个独特的社区资源，一组来自患者的HiPSC细胞，可以用来 评估PAE在整个生命周期内的系统性影响；其次，扩大了我们对 PAE对干细胞行为的影响；第三，确定了早衰的重要细胞机制。

Project Summary: Prenatal alcohol exposure (PAE) is common and can result in brain-based disabilities and growth deficits. The impact of PAE is not just in early development, but also can lead to secondary health problems throughout the lifespan. These secondary problems can include higher rate and earlier onset of aging-related diseases, including cardiovascular disease, autoimmune disorders such as arthritis, and decreased bone density. The early onset of these aging-related diseases indicates that a consequence of PAE is premature aging of tissues and organs. There is an unmet need to better understand this PAE-induced premature aging and determine the underlying mechanisms that could be leveraged to delay or prevent these secondary health conditions. We know that PAE is a potent teratogen that reprograms stem cells. Our hypothesis is that this stem cell reprogramming has lifelong consequences, including the premature aging of stem cells as a mechanism that drives systemic aging. This hypothesis is supported by published literature that shows PAE can disrupt stem cell self-renewal, due, in part, to premature or aberrant differentiation, and that these disrupted stem cell behaviors persist into adulthood. Based on these data, we plan to address two questions: firstly, “does PAE in human populations diminish stem cell function across the lifespan?”; secondly, “does PAE induce or exacerbate human stem cell aging?”. To address the above two questions, we plan to create human induced pluripotent stem cells (hiPSCs), as early passages of these cells retain epigenetic markers of aging. These cells will be derived from regionally and ethnically diverse neonatal, child/adolescent, and adult cohorts of individuals with PAE/fetal alcohol spectrum disorders (FASDs) and from matched controls. In Aim 1 we plan to use a panel of cellular and molecular assays to assess PAE/FASD-induced changes in stem cell growth, self-renewal, and trilineage (ectoderm, mesoderm, endoderm) differentiation. In Aim 2 we plan to assess alterations to stem cell aging, including exhaustion, senescence, and release of pro-inflammatory molecules as part of the senescence- associated secretory phenotype. Our overarching goal, to ultimately identify underlying mechanisms mediate the emergence of secondary health conditions for individuals with FASDs, is consistent with the mission of the NIAAA (RFA-AA-21-014). PAE is known to inhibit stem cell function. However, tissue stem cells may also be a novel target for the prevention and treatment of PAE-induced premature aging. At the conclusion of these studies, we will have: firstly, created a unique community resource, a panel of patient-derived hiPSC cells, that can be used to assess the systemic impact of PAE across the lifespan; secondly, expanded our knowledge of the impact of PAE on stem cell behavior; and thirdly, identified important cellular mechanisms of premature aging.