The role of Type 3 deiodinase in Brain Sexual Differentiation

描述(由申请人提供)：尽管许多精神疾病的病因仍很不清楚，但公认这些疾病的潜在原因涉及多种遗传和环境因素。大多数这些疾病的患病率存在明显的性别偏见，这表明大脑的性别分化和/或大脑中的性类固醇作用机制可能对他们的病理生理起到了作用。众所周知，甲状腺激素(TH)在发育中的大脑中发挥着深远的作用，并在该组织中拮抗雌激素(E)在基因表达和行为调节中的作用。强大的体内平衡机制已经到位，以确保TH浓度适合特定发育阶段的特定大脑区域。其中一个机制是3型脱碘酶(D3)，这是一种降解TH的酶。D3在发育中的大脑和成年大脑中高度表达，并由印记基因编码。在我们实验室产生的D3缺陷小鼠中的初步结果表明，D3是包括下丘脑在内的大多数大脑区域充分表达TH状态和TH依赖基因所必需的。缺乏活跃的D3还会导致大脑结构的改变，异常的社交行为，以及与行为功能相关的某些神经肽水平的下降。目前探索性和发展研究补助金(R21)申请的目标是确定3型脱碘酶(D3)在大脑性别分化和/或该组织中的性类固醇作用中的作用。利用D3缺陷小鼠，我建议i)确定D3和TH在发育中和成人大脑中E动作的不同范例中的调节功能；以及ii)确定D3缺乏对选定的与行为相关的神经肽的E依赖调节和性二型性的影响。这些初步研究可能确定D3是一种参与大脑性别分化的新因素，并可能指出大脑中TH代谢和活动的改变是影响大脑发育和功能以及决定成人行为的重要过程。这些研究可能会打开一个新的研究领域，研究神经疾病的神经生物学机制。由于这些发现可能适用于人类，这项研究和未来的研究可能为旨在预防和治疗发育和精神障碍的治疗干预提供新的目标。公共卫生相关性：建议的研究将使用正常小鼠和缺乏3型脱碘酶的小鼠来确定这种酶是否在发育中和/或成人大脑中调节性类固醇活动，从而影响大脑的性别分化和中枢神经系统中性二型性特征的产生。这一假说的证实将提供一种新的机制，可能有助于揭示人类某些神经疾病的病因学和病理生理学，这些疾病表现出性别偏见，并以异常行为为特征，如自闭症、精神分裂症、双相情感障碍、抑郁症等。

DESCRIPTION (provided by applicant): Although the etiology of many psychiatric disorders remains largely unknown, it is accepted that the underlying causes of these pathologies involve multiple genetic and environmental factors. The marked gender bias in the prevalence of most of these conditions suggests that mechanisms of brain sexual differentiation and/or sex steroid action in the brain might be contributing to their pathophysiology. Thyroid hormones (TH) are known to exert profound effects in the developing brain as well as to antagonize in this tissue the action of estrogen (E) in the regulation of gene expression and behavior. Robust homeostatic mechanisms are in place to ensure that TH concentrations are appropriate for a particular brain region at a specific developmental stage. One of these mechanisms is the type 3 deiodinase (D3), an enzyme that degrades TH. D3 is highly expressed in the developing and adult brain and is encoded by an imprinted gene. Preliminary results in D3-deficient mice generated in our laboratory indicate that D3 is necessary for adequate TH status and TH-dependent gene expression in most brain regions, including the hypothalamus. The lack of an active D3 also results in alterations in brain structure, abnormal social behavior and decreased levels of certain neuropeptides related to behavioral functions. The goal of the present Exploratory and developmental Research Grant (R21) application is to determine the role of the type 3 deiodinase (D3) in the sexual differentiation of the brain and/or in sex steroid action in this tissue. Using D3-deficient mice, I propose i) To define the regulatory functions of D3 and TH in various paradigms of E action in the developing and adult brain; and ii) To determine the effect of D3 deficiency on the E-dependent regulation and sexual dimorphism of selected neuropeptides related to behavior. These initial studies may identify D3 as a novel factor involved in the sexual differentiation of the brain and may point to altered TH metabolism and action in the brain as an important process influencing brain development and function and determining adult behavior. These studies may open a new area of research into the mechanisms contributing to the neurobiology of neurological disorders. As these findings may apply to humans, this and future studies may provide novel targets for therapeutic interventions aimed at preventing and treating developmental and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The studies proposed will use normal mice and mice deficient in the type 3 deiodinase to determine whether this enzyme has a role in regulating sex steroid action in the developing and/or adult brain and therefore affects brain sexual differentiation and the generation of sexually dimorphic features in the central nervous system. The confirmation of this hypothesis will provide a novel mechanism that may shed some light into the etiology and pathophysiology of certain neurological conditions in humans that exhibit a gender bias and that are characterized by abnormal behavior, such as autism, schizophrenia, bipolar disorder, depression and others.