Aneuploid fetal microchimerism: persistence and potential function

项目总结： 在人类怀孕期间，母亲和胎儿交换细胞，这些细胞可以持久地作为 微嵌合体，在另一个个体中存在少量的外来遗传物质。胎儿微嵌合症 已经被多个调查人员证明与母亲晚年的健康有关，包括 既有疾病的风险，又有预防疾病的能力。这些关系的复杂性可能会在以下情况下进一步放大 胎儿微嵌合体在遗传上是不正常的。21三体，或称唐氏综合症，是最常见的 常见的胎儿遗传异常。一些已知与唐氏综合症直接相关的疾病风险 唐氏综合症女性后代的健康状况也反映了唐氏综合症的症状。例如，具有以下特征的个人 唐氏综合症是阿尔茨海默病的高危人群。有趣的是，唐人街的母亲 研究表明，患有阿尔茨海默氏症的后代本身就会增加阿尔茨海默病的发病率。这个 这种关联的原因尚不清楚；然而，一种假设是，遗传异常的微嵌合体细胞 可能会成为疾病的死穴。另一方面，来自21三体胎儿的微嵌合体也可能具有 潜在的益处，特别是与恶性肿瘤风险有关的风险。唐氏综合症患者显著 实体肿瘤的风险低于预期，尤其是乳腺癌。总的来说，胎儿微嵌合体一直是 被证明对乳腺癌的发展具有保护作用；一些人假设这种关系反映了 来自微嵌合“移植物”的额外免疫监测，以消除癌前细胞。这些 观察提出了这样一个问题：21三体妊娠的微嵌合体是否会转化为 当母亲获得细胞时的额外保护，特别是对实体肿瘤的发展具有保护作用。至 直接牵涉到基因异常的微嵌合体作为一个促成因素，它在怀孕后的持久性 它的功能能力必须得到证明。这项建议旨在识别胎儿微嵌合体 妊娠合并21三体的妇女和直接评估基因构成 和微嵌合体细胞的基因表达。如果得到证实，来自这些研究的信息可能会产生目标 用于治疗，以最大限度地提高暴露于基因异常微嵌合体的妇女的健康水平，以及 更宽泛的人口定义。从这项工作中获得的见解对那些拥有 经历了21三体妊娠，对于他们的后代来说，就疾病机制而言， 据了解，受阿尔茨海默氏症和乳腺癌等疾病影响的人群更多。

Project Summary: A mother and fetus exchange cells during human pregnancy, and these cells can durably persist as microchimerism, a small amount of foreign genetic material in another individual. Fetal microchimerism has been demonstrated by multiple investigators to be associated with later-life health for the mother, including both risk for and protection from disease. The complexity of these relationships may be further amplified when the fetal microchimerism is genetically abnormal. Trisomy 21, or Down Syndrome, is one of the most commonly seen fetal genetic abnormalities. Some disease risks known to be directly associated with Down Syndrome are reflected in the health of women with Down Syndrome offspring. For example, individuals with Down Syndrome are at high risk for the development of Alzheimer’s Disease. Interestingly, mothers of Down Syndrome offspring have been shown to have an increased incidence of Alzheimer’s Disease themselves. The cause of this association is unknown; however, one hypothesis is that genetically abnormal microchimeric cells could serve as a nidus for disease. On the other hand, microchimerism from a Trisomy 21 fetus may also have potential benefit, particularly related to risk of malignancy. Individuals with Down Syndrome have significantly lower than expected risks of solid tumors, especially breast cancer. In general, fetal microchimerism has been shown to be protective for the development of breast cancer; some hypothesize this relationship to reflect additional immune surveillance from the microchimeric “graft” for elimination of precancerous cells. These observations raise the question whether microchimerism from a Trisomy 21 pregnancy may translate into additional protection when the mother acquires cells particularly protective for solid tumor development. To directly implicate genetically abnormal microchimerism as a contributing factor, its persistence after pregnancy and its functional capacity must be demonstrated. This proposal aims to identify fetal microchimerism in women who have had a pregnancy complicated by Trisomy 21 and to directly evaluate the genetic makeup and gene expression of microchimeric cells. If demonstrated, information from these studies could yield targets for therapy to maximize health in women with exposure to genetically abnormal microchimerism, as well as for more broadly defined populations. Insights gained from this work have potential benefit for women who have experienced a Trisomy 21 pregnancy, for their offspring directly, and, insofar as mechanisms of disease can be elucidated, the larger populations affected by diseases including Alzheimer’s Disease and breast cancer.