Lifelong impact of PAE on stem cell dynamics and cellular aging

项目摘要： 产前酒精暴露（PAE）很常见，可导致大脑残疾和生长缺陷。的 PAE的影响不仅仅是在早期发展，而且还可能导致整个过程中的继发性健康问题。 寿命这些继发性问题可能包括与衰老有关的疾病的发病率较高和发病较早， 包括心血管疾病、自身免疫性疾病如关节炎和骨密度降低。的 这些与衰老有关的疾病的早期发作表明PAE的后果是组织的过早衰老 和器官。有一个未满足的需要，以更好地了解这种PAE诱导的过早衰老，并确定 可以用来延缓或预防这些继发性健康状况的潜在机制。 我们知道PAE是一种强有力的致畸剂，可以重新编程干细胞。我们的假设是这种干细胞 重新编程具有终身的后果，包括干细胞的过早老化作为一种机制， 导致系统老化已发表的文献支持这一假设，表明PAE可破坏股骨柄 细胞自我更新，部分原因是过早或异常分化，这些破坏的干细胞 行为持续到成年。基于这些数据，我们计划解决两个问题：第一，“PAE是否在 人类人口在整个生命周期中减少干细胞功能？";第二，“PAE是否诱导或 人类干细胞衰老的原因是什么？ 为了解决上述两个问题，我们计划创造人类诱导多能干细胞（hiPSC）， 这些细胞的早期传代保留了衰老的表观遗传标记。这些细胞将来自区域性的 不同种族的新生儿、儿童/青少年和成人PAE/胎儿酒精患者队列 谱系障碍（FASD）和匹配的对照。在目标1中，我们计划使用一个蜂窝面板， 评估PAE/FASD诱导的干细胞生长、自我更新和三系变化的分子测定 （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衰老的改变， 包括疲惫、衰老和作为衰老一部分的促炎分子的释放- 相关分泌表型。 我们的总体目标是最终确定介导继发性 FASD患者的健康状况与NIAAA的使命一致（RFA-AA-21-014）。 已知PAE抑制干细胞功能。然而，组织干细胞也可能是一个新的目标， 预防和治疗PAE引起的过早衰老。在这些研究结束时，我们将有： 首先，创建了一个独特的社区资源，一组患者来源的hiPSC细胞，可用于 评估PAE在整个生命周期中的系统影响;其次，扩大了我们对 PAE对干细胞行为的影响;第三，确定了过早衰老的重要细胞机制。

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.