Exploring the role of neuroactive steroids in Tourette syndrome

探索神经活性类固醇在抽动秽语综合征中的作用

基本信息

批准号：
10656348
负责人：
Marco Bortolato
金额：
$ 19.67万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656348
关键词：
12 year old Address Adolescence Adrenal Glands Adult Affect Age Age of Onset Allopregnanolone Animal Model Behavior Therapy Behavioral Biologic Characteristic Biological Biology Child Clinical Clinical Research Development Disease Dose Endocrine Exhibits Family Female Foundations Funding Gilles de la Tourette syndrome Hydrocortisone Investigation Knowledge Mass Spectrum Analysis Measures Mediator Metabolic Pathway Metabolism Motor Neurodevelopmental Disorder Neurosecretory Systems Participant Pathway interactions Patients Pharmaceutical Preparations Phase Pilot Projects Positioning Attribute Predisposition Prefrontal Cortex Process Regulation Role Safety Saliva Salivary Sampling Severities Sex Differences Specimen Steroids Stress Sulfate Symptoms Testing Urine Variant acute stress associated symptom biological adaptation to stress boys clinical investigation dehydroepiandrosterone girls improved male mouse model neuromechanism neurosteroids novel novel therapeutics patient response perceived stress potential biomarker response sex sound specific biomarkers stress reduction therapeutic target tic suppression trait treatment strategy urinary

项目摘要

ABSTRACT / PROJECT SUMMARY Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by motor and phonic tics. Available treatment strategies remain unsatisfactory, due to our limited knowledge of the biological foundations of this disorder. The studies proposed in this application will explore the mechanisms underlying two of the least well-understood biological characteristics of TS, namely its marked male predominance and stress sus- ceptibility. Studies from our group suggest that these features of TS are contributed by neuroactive steroids, a family of mediators implicated in sex and stress regulation. The typical age of onset of TS is 6-7 years, coinciding with adrenarche, a phase of adrenal maturation charac- terized by an upsurge in adrenal neuroactive steroids, such as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In preliminary studies, we found that DHEA exacerbated tic-like responses in animal models of TS. Interestingly, the dose of DHEA needed to elicit TS-like responses in females is higher than those needed in males, possibly pointing to a mechanism of sex differences in TS. Stress reduces the ability of TS patients to suppress tics, but the underlying mechanisms remain unknown. Our studies in animal models indicate that this process may be due to the elevation of the neuroactive steroid allo- pregnanolone (AP) in the prefrontal cortex. By inhibiting the ability of the prefrontal cortex to suppress tics, AP promotes tic execution. In a pilot study, we found that tic suppression, a well-known stressful task in TS pa- tients, increases AP salivary levels. Furthermore, in another proof-of-concept study, we found that inhibiting AP synthesis led to a reduction in tic severity and facilitated voluntary control of tics in stressful situations. These findings lead us to hypothesize that TS patients exhibit alterations of the composition of their neuroac- tive steroid profiles, including: 1) an increase in baseline DHEA(S) levels in male TS patients, in correlation with lifetime severity; and 2) an exaggerated elevation in AP in response to acute stress. The two Aims of this proposal will test this hypothesis by: 1) comparing the baseline urinary steroidomic profile of TS-affected boys and girls with non-affected sex- and age-matched controls; and 2) charting the dynamic alterations in steroidomic salivary profiles in response to tic suppression. These studies will advance our un- derstanding of the endocrine mechanisms in TS and lead to the identification of potential biomarkers for the severity of tics and comorbid symptoms. In the long run, the results of these studies may open the way for the development of new therapies for TS that may reduce tic severity and increase patients' responsiveness to be- havioral interventions.

摘要/项目摘要抽动秽语综合征 (TS) 是一种致残性神经发育障碍，其特征是运动和发声抽搐。由于我们对生物学基础的了解有限，现有的治疗策略仍然不能令人满意这种疾病。本申请中提出的研究将探索其中两种的潜在机制 TS 的生物学特征最不为人所知，即其明显的男性优势和应激承受能力感受性。我们小组的研究表明 TS 的这些特征是由神经活性类固醇造成的，与性和压力调节有关的调解者家族。 TS 的典型发病年龄为 6-7 岁，恰逢肾上腺初现，这是肾上腺成熟的一个阶段。肾上腺神经活性类固醇的激增，例如脱氢表雄酮 (DHEA) 及其硫酸盐（DHEAS）。在初步研究中，我们发现 DHEA 加剧了 TS 动物模型的抽动样反应。有趣的是，在女性中引发类似 TS 反应所需的 DHEA 剂量高于在女性中所需的剂量。男性，可能指出了 TS 性别差异的机制。压力会降低 TS 患者抑制抽动的能力，但其潜在机制仍不清楚。我们的动物模型研究表明，这一过程可能是由于神经活性类固醇同种异体的升高所致。前额皮质中的孕酮（AP）。通过抑制前额皮质抑制抽动的能力，AP 促进抽动执行。在一项初步研究中，我们发现抽动抑制是 TS 患者中众所周知的压力任务。 tents，增加AP唾液水平。此外，在另一项概念验证研究中，我们发现抑制 AP 合成导致抽动严重程度降低，并有助于在压力情况下自愿控制抽动。这些发现使我们推测 TS 患者的神经活性成分发生了改变。活性类固醇概况，包括：1) 男性 TS 患者基线 DHEA(S) 水平增加，相关性终生严重； 2) AP 因急性应激而过度升高。该提案的两个目标将通过以下方式检验这一假设：1) 比较基线尿类固醇谱受 TS 影响的男孩和女孩与未受影响的性别和年龄匹配的对照； 2）绘制动态图表类固醇唾液谱的变化响应抽动抑制。这些研究将推动我们的了解 TS 的内分泌机制并确定潜在的生物标志物抽动和合并症症状的严重程度。从长远来看，这些研究结果可能为开发治疗 TS 的新疗法，可以减轻抽动的严重程度并提高患者的反应能力行为干预。