Steroid signaling in the choroid plexus of the aging brain

衰老大脑脉络丛中的类固醇信号传导

• 批准号: 10117618
• 负责人: Jennifer L Garrison
• 金额: $ 27.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117618
• 关键词: Ablation; Acute; Adult; Affect; Age; Aging; Alzheimer' s Disease; Animal Model; Applications Grants; Blood capillaries; Brain; CRISPR interference; Calcium; Calcium Channel; Calcium-Binding Proteins; Caliber; Cell membrane; Cerebral Ventricles; Cerebrospinal Fluid; Choroid Plexus Epithelium; Data; Development; Disease; Disease susceptibility; Effectiveness; Enzymes; Epithelial; Estrogens; Failure; Female; Fluid Balance; Functional disorder; Gene Expression; Genes; Gonadal Steroid Hormones; Hormones; Hydrolase; Impaired cognition; Ion Channel; Joints; Knock-out; Link; Liquid substance; MGP gene; Membrane; Menopause; Molecular; Molecular Disease; Molecular Target; Mus; Neuroprotective Agents; Nuclear; Nutrient; Outcome; Outcomes Research; Pathway interactions; Physiological; Physiology; Play; Predisposition; Production; Progesterone; Progesterone Receptors; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Steroids; Structure of choroid plexus; Tissues; Vascular calcification; Waste Products; Woman; Work; age related; aging brain; biophysical properties; calcification; cerebrospinal fluid flow; cognitive development; conditional knockout; early onset; gender difference; knock-down; men; novel; prevent; progesterone receptor A; sexual dimorphism; steroid hormone; steroid hormone receptor; therapy development

Recent studies have found that women are bearing a disproportionate amount of the Alzheimer’s disease this disease it produces less progesterone and estrogens and there is a correlation between early onset of menopause (and hence a decline in sex steroid levels) with increased Alzheimer’s disease susceptibility. Steroid hormones regulate physiology of many tissues, among which is the choroid plexus- an epithelial tissue responsible for secretion of cerebrospinal fluid (CSF), the fluid that protects the brain, provides it with nutrients and hormones, and removes waste products. With aging, the choroid plexus fails to maintain adequate CSF production and turnover and this may contribute to the onset of cognitive decline and development of the Alzheimer’s disease the molecular mechanism of its action remains burden: at the age of 65, women have a 1 in 5 chance of developing , compared to a 1 in 11 chance for men. As the female body ages, . Steroid hormone progesterone is known to regulate fluid homeostasis in the choroid plexus, however, elusive. We recently discovered that while choroid plexus does not express any canonical nuclear-localized progesterone receptors, it does highly express the unconventional membrane progesterone receptor α/β hydrolase domain–containing protein 2 (ABHD2). Global knockout of Abhd2 produces mice with smaller brain ventricles and narrower choroid plexus capillaries. Our preliminary data indicate the steroid signaling in the choroid plexus , and since steroid levels decline with age, turnover of CSF production may be altered by a narrower choroid plexus capillary network due to decreased steroid content. we seek to study (1) the physiological role of ABHD2 and its downstream effectors in the choroid plexus of the aging brain by generating conditional knockouts of Abhd2 and other targeted genes specifically in the choroid plexus; and (2) to explore the mechanism between CSF turnover with age and the role steroid hormones play in it. Our team has matching expertise in acute tissue-specific gene knockdown in the aging mouse brain and biophysical characterization of the choroid plexus function. The outcome of this research will help to establish physiological role of ABHD2 in the choroid plexus and its alteration during aging and Alzheimer’s disease. Additionally, this work will reveal novel could be linked to CSF turnover Here molecular pathways that may explain gender- differences in steroid regulation of CSF production and why Alzheimer’s disease affects women at a higher rate. Finally, data obtained from this project will form the basis for a joint R01 grant application, which will allow us to expand our teams’ research on steroid regulation of the brain function and its role in Alzheimer’s disease.

最近的研究发现，妇女承担了不成比例的 阿尔茨海默病 这种疾病 它产生较少的孕酮和雌激素， 绝经早期发生（因此性类固醇水平下降）与增加 阿尔茨海默病易感性。类固醇激素调节许多组织的生理学，其中之一是 脉络丛-一种负责分泌脑脊液（CSF）的上皮组织，脑脊液保护神经细胞， 大脑，为它提供营养和激素，并清除废物。随着年龄的增长，脉络膜 神经丛不能维持足够的CSF产生和周转，这可能导致 认知能力下降和阿尔茨海默病的发展 其作用的分子机制仍然存在 负担：在65岁时，女性有五分之一的机会发展，相比之下， 男人的机会随着女性身体的衰老， .已知类固醇激素孕酮 然而，调节脉络丛中的液体稳态， 难以捉摸。 我们最近发现，虽然脉络丛不表达任何典型的核定位， 孕激素受体，它确实高度表达非常规膜孕激素受体α/β 含水解酶结构域蛋白2（ABHD 2）。全球淘汰赛 Abhd 2产生小鼠， 小脑 脑室和狭窄 脉络丛 毛细血管。我们的初步数据表明， 脉络丛，并且由于类固醇水平随年龄下降，CSF的周转 由于类固醇含量降低，产生可能被更窄的脉络丛毛细血管网改变。 我们试图研究（1）ABHD 2及其下游效应物在脉络丛中的生理作用， 通过产生条件性敲除Abhd 2和其他靶基因， （2）探讨脑脊液更新与年龄的关系及激素的作用机制 我们的团队在衰老过程中的急性组织特异性基因敲除方面具有匹配的专业知识， 小鼠脑和脉络丛功能的生物物理表征。这项研究的结果将 有助于建立ABHD 2在脉络丛中的生理作用及其在衰老过程中的变化， 老年痴呆症此外，这项工作将揭示新的 可能与脑脊液周转有关 这里 可以解释性别的分子途径 类固醇调节CSF产生的差异以及为什么阿尔茨海默病影响女性的原因 率最后， 从该项目获得的数据将构成联合R 01赠款申请的基础，这将允许 我们将扩大我们团队对类固醇调节脑功能及其在阿尔茨海默病中的作用的研究。