Embryo Transfer for the Study of Transgenerational Modifications in Morphine Sens

用于吗啡敏感跨代修饰研究的胚胎移植

基本信息

批准号：
8601067
负责人：
ELIZABETH M BYRNES
金额：
$ 8.25万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8601067
关键词：
Absence of pain sensation Adolescence Adolescent Adolescent Development Adult Adult Children Alcohol or Other Drugs use Alcohols Animal Model Assisted Reproductive Technology Behavioral Cells Characteristics Child Collection Complex Corticosterone DNA DNA Methylation DNA Sequence Dependence Development Dose Drug abuse Embryo Embryo Transfer Environment Environmental Risk Factor Epigenetic Process Family Female Female Adolescents Fertility Future Gene Expression Generations Genes Genetic Goals Growth Histones Human Inherited Intervention Lead Measures Mediating Modeling Modification Morphine Mothers Narcotics Nature Operative Surgical Procedures Opiates Parents Partner in relationship Pattern Perinatal Exposure Pharmaceutical Preparations Physiological Play Population Post-Translational Protein Processing Pregnancy Rattus Risk Factors Role Running Sexual Maturation Sprague-Dawley Rats Substance abuse problem Techniques Vagina Work base daughter cell drug of abuse experience flexibility offspring postnatal prenatal public health relevance pup reproductive research study response success transmission process

项目摘要

DESCRIPTION (provided by applicant): Many studies demonstrate that the hereditary nature of drug abuse is due to both genetic and environmental factors. One mechanism regulating interactions between genes and the environment are epigenetic modifications. In this context, the term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell, or from a parent to its progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well-studied. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that, in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. One important aspect of this model is that adolescent morphine- exposed females are drug-free for several weeks prior to mating, and thus there is no direct in utero exposure. The purpose of this proposal is to develop, refine, and implement non-surgical embryo transfer in females exposed to morphine during adolescent development. This technique will then be used to delineate offspring effects that are directly mediated by modifications at the level of the embryo from those induced by alterations in the pre- and/or postnatal environment. The primary focus will be on transgenerational alterations in morphine sensitivity (behavioral and physiological) as these effects are well-characterized. Moreover, understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next may help identify basic mechanisms underlying familial patterns of substance use.

描述（由申请人提供）：许多研究表明，药物滥用的遗传性是由遗传和环境因素造成的。调节基因与环境之间相互作用的一种机制是表观遗传修饰。在本文中，表观遗传学一词是指调节基因表达的 DNA 和组蛋白修饰，这些修饰从母细胞传递到子细胞，或从亲本传递到其子代，但不会改变潜在的 DNA 序列。虽然很明显表观遗传修饰可以从一代传到下一代，但这些效应传递所涉及的机制尚不完全清楚。最近的一些研究结果表明，产前和产后的母体环境可能在表观遗传转移中发挥关键作用。迄今为止，表观遗传学在药物滥用家族模式中的作用尚未得到充分研究。我们开发了雌性大鼠青春期吗啡暴露的动物模型，以检查在这个独特的发育时期使用阿片类药物的长期后果。我们的研究结果表明，除了在青春期暴露于吗啡的成年雌性大鼠的基因表达发生显着变化外，青少年暴露于吗啡的雌性大鼠的后代也表现出对吗啡的反应性增强。该模型的一个重要方面是，暴露于吗啡的青春期雌性在交配前几周内没有吸毒，因此不存在直接的子宫内暴露。该提案的目的是为青春期发育期间接触吗啡的女性开发、完善和实施非手术胚胎移植。然后，该技术将用于描绘由胚胎水平的修饰直接介导的后代效应由产前和/或产后环境的改变引起。主要焦点将是吗啡敏感性（行为和生理）的跨代改变，因为这些影响已得到充分表征。此外，了解药物引起的吗啡敏感性改变如何从一代传到下一代可能有助于确定药物滥用家族模式的基本机制。