Aneuploid fetal microchimerism: persistence and potential function

项目摘要： 在人类怀孕期间，母亲和胎儿交换细胞，这些细胞可以持久存在， 微嵌合体，即在另一个个体中存在少量外来遗传物质。胎儿微嵌合体 多名研究人员已证明与母亲的晚年健康有关，包括 既能预防疾病又能预防疾病这些关系的复杂性可能会进一步放大， 胎儿微嵌合体是遗传异常。21三体综合征，或唐氏综合征，是最常见的 常见的胎儿遗传异常。已知与唐氏症直接相关的一些疾病风险 唐氏综合症的健康状况反映在患有唐氏综合症的女性后代身上。例如，患有 唐氏综合症是阿尔茨海默氏症的高风险发展。有趣的是唐氏症的母亲们 综合征的后代已经被证明有一个增加的发病率阿尔茨海默氏病本身。的 这种关联的原因尚不清楚;然而，一种假设是，遗传异常的微嵌合细胞 可能成为疾病的温床另一方面，来自21三体胎儿的微嵌合体也可能具有 潜在获益，特别是与恶性肿瘤风险相关的获益。唐氏综合症患者有明显的 低于预期的实体瘤风险，尤其是乳腺癌。一般来说，胎儿微嵌合体已经被 显示对乳腺癌的发展有保护作用;一些人假设这种关系反映了 来自微嵌合体“移植物”的额外免疫监视用于消除癌前细胞。这些 观察提出了一个问题，21三体妊娠的微嵌合体是否可以转化为 当母亲获得对实体瘤发展具有特别保护作用的细胞时，可提供额外的保护。到 直接暗示遗传异常微嵌合体作为一个促成因素，其持续怀孕后， 必须证明其功能能力。这项建议旨在确定胎儿微嵌合体， 患有21三体综合征的孕妇，并直接评估基因组成， 和微嵌合细胞的基因表达。如果得到证实，这些研究的信息可以产生目标， 用于治疗暴露于遗传异常微嵌合体的女性， 更广泛地定义人口。从这项工作中获得的见解对妇女有潜在的好处， 经历了21三体妊娠，直接为他们的后代，而且，只要疾病的机制可以是 阐明，更大的人口受疾病，包括阿尔茨海默病和乳腺癌的影响。

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.