Lifelong impact of PAE on stem cell dynamics and cellular aging

PAE 对干细胞动力学和细胞衰老的终生影响

• 批准号: 10470507
• 负责人: Amanda H. Mahnke
• 金额: $ 22.04万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470507
• 关键词: Address; Adolescent; Adolescent and Young Adult; Adult; Age; Aging; Animal Model; Arthritis; Autoimmune Diseases; Base of the Brain; Bayesian Modeling; Biological Assay; Bone Density; Brain region; Canada; Cardiovascular Diseases; Cell Aging; Cell Line; Cells; Child; Childhood; Chronology; Clinical; Collaborations; Communities; Data; Development; Disease; Ectoderm; Endoderm; Epigenetic Process; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Future; Geography; Goals; Growth; Health; Human; Immunologic Markers; Individual; Inflammatory; Intervention; Knowledge; Laboratories; Lead; Letters; Life Expectancy; Link; Literature; Longevity; Mediating; Mesoderm; Mission; Mitotic; Molecular; National Institute on Alcohol Abuse and Alcoholism; Neonatal; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neurologic; Organ; Outcome; Patient Self-Report; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Premature aging syndrome; Prevention; Public Health; Publishing; Regenerative capacity; Research; Resources; Russia; Secondary to; Source; Stress; Surveys; Teratogens; Testing; Tissues; Translating; Ukraine; Vendor; alcohol exposure; base; cell behavior; cohort; comorbidity; disability; early onset; epigenetic marker; ethnic diversity; exhaustion; human stem cells; improved; induced pluripotent stem cell; infancy; innovation; male; neonate; novel; novel therapeutic intervention; patient population; premature; prevent; self-renewal; senescence; sex; stem cell aging; stem cell biomarkers; stem cell division; stem cell function; stem cell growth; stem cell self renewal; stem cells; tissue stem cells

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.

项目摘要： 产前酒精暴露（PAE）很常见，可能导致脑基疾病并增加缺乏症。这 PAE的影响不仅在早期发展中，而且还可能导致整个过程中的二级健康问题 寿命。这些次要问题可能包括更高的率和早期发作与衰老有关的疾病， 包括心血管疾病，自身免疫性疾病，例如关节炎和骨密度降低。 这些与衰老有关的疾病的早期发作表明，PAE的结果是组织的过早衰老 和器官。有未满足的需要更好地理解这种PAE引起的过早衰老和确定 可以利用的基本机制来延迟或防止这些继发健康状况。 我们知道，PAE是重编程干细胞的潜在致畸。我们的假设是该干细胞 重编程具有终生后果，包括干细胞的过早衰老作为一种机制 驱动系统性衰老。该假设得到了已发表的文献的支持，该文献表明PAE可能会破坏STEM 细胞自我更新，部分原因是由于过早或异常分化，并且这些干扰了干细胞 行为持续到成年。基于这些数据，我们计划解决两个问题：首先： 人群降低了整个寿命的干细胞功能吗？”；其次，“ Pae诱导或 加剧人类干细胞衰老吗？”。 为了解决以上两个问题，我们计划创建人类诱导的多能干细胞（HIPSC），例如 这些细胞的早期通过保留了衰老的表观遗传标记。这些单元将源自区域 以及种族多样的新生儿，儿童/青少年和成年人群，患有PAE/胎儿酒精的人群 频谱障碍（FASD）和来自匹配的控件。在AIM 1中，我们计划使用一组细胞和 分子测定法评估PAE/FASD诱导的干细胞生长，自我更新和Trilineage的变化 （外胚层，中胚层，内胚层）分化。在AIM 2中，我们计划评估干细胞衰老的改变， 包括精疲力尽，感应和促炎分子的释放，作为感应的一部分 相关的秘密表型。 我们的总体目标，最终确定基本机制介导了次要的出现 FASD患者的健康状况与NIAAA的任务一致（RFA-AA-21-014）。 已知PAE抑制干细胞功能。但是，组织干细胞也可能是 预防和治疗PAE诱导的过早衰老。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在整个寿命中的系统影响；其次，扩大了我们对影响的知识 对干细胞行为的PAE；第三，确定了过早衰老的重要细胞机制。