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在很大程度上仍然未知，但公认这些病理的根本原因涉及多种遗传和环境因素。在大多数这些条件的患病率显着的性别偏见表明，大脑性别分化和/或性类固醇作用的机制在大脑中可能有助于他们的病理生理。已知甲状腺激素（TH）在发育中的大脑中发挥深远的作用，以及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。稳健的稳态机制是适当的，以确保TH浓度适合于特定发育阶段的特定大脑区域。这些机制之一是3型脱碘酶（D3），一种降解TH的酶。D3在发育和成人大脑中高度表达，由印记基因编码。在我们的实验室中产生的D3缺陷小鼠的初步结果表明，D3是必要的足够的TH状态和TH依赖的基因表达在大多数大脑区域，包括下丘脑。缺乏活跃的D3也会导致大脑结构的改变，异常的社会行为和与行为功能相关的某些神经肽水平的降低。本探索和发展研究资助（R21）申请的目标是确定3型脱碘酶（D3）在大脑性别分化和/或该组织中性类固醇作用中的作用。使用D3缺陷小鼠，我建议i）定义的调节功能的D3和TH在各种范式的E行动在发展和成人的大脑;和ii）确定D3缺陷的影响，E依赖的调节和性二态性的选择神经肽相关的行为。这些初步的研究可能会确定D3作为一个新的因素参与性别分化的大脑，并可能指向改变TH代谢和行动在大脑中作为一个重要的过程，影响大脑的发育和功能，并决定成年人的行为。这些研究可能为神经系统疾病的神经生物学机制开辟一个新的研究领域。由于这些发现可能适用于人类，因此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疾病的治疗干预提供新的靶点。公共卫生相关性：拟议的研究将使用正常小鼠和缺乏3型脱碘酶的小鼠，以确定这种酶是否在调节发育和/或成年大脑中的性类固醇作用中起作用，从而影响大脑性别分化和中枢神经系统中性二态特征的产生。这一假设的证实将提供一种新的机制，可能揭示人类某些神经系统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.