Investigating Autonomic Dysfunction as an Early Pathologic Feature of Huntington’s Disease

研究自主神经功能障碍作为亨廷顿病的早期病理特征

基本信息

批准号：
10360540
负责人：
Jordan Schultz
金额：
$ 17.94万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360540
关键词：
18 year old Adrenergic beta-Antagonists Adult Age Age of Onset Anterior Area Atrophic Autonomic Dysfunction Autonomic nervous system Back Baroreflex Biometry Blood Pressure Body Temperature Brain Brain region Cardiovascular system Carotid Arteries Cerebrovascular Circulation Cerebrovascular system Child Chronic Complication Corpus striatum structure Disease Disease Progression Ensure Equilibrium Etiology Exhibits Family Functional Magnetic Resonance Imaging Functional disorder Funding Gene therapy trial Genes Goals Grant Heart Rate Homeostasis Huntington Disease Huntington gene Huntington protein Hypertension Insula of Reil Iowa K-Series Research Career Programs Location Magnetic Resonance Imaging Measures Mentors Mentorship Methods Modification Motor National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous System Physiology Neurobiology Neurodegenerative Disorders Outcome Participant Pathologic Patient Recruitments Patients Pharmaceutical Preparations Pharmacists Pharmacology Physiological Plasma Positioning Attribute Prefrontal Cortex Principal Investigator Publishing Recording of previous events Reporting Research Research Personnel Research Training Rest Risk Sampling Seeds Signal Transduction Structure Sympathetic Nerve Block Sympathetic Nervous System Symptoms Testing Therapeutic Thinness Time Training Training Programs Trinucleotide Repeats Vascular System aged arterial spin labeling arterial stiffness base beta-adrenergic receptor blood oxygen level dependent career career development cingulate cortex experience experimental study gene therapy heart rate variability improved mutant neurodevelopment neurofilament protein L neuroimaging new therapeutic target novel novel therapeutics patient oriented patient population prevent success targeted biomarker therapeutic target translational scientist

项目摘要

Project Summary/Abstract The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to support my short-term career objective of determining if dysfunction of the autonomic nervous system (ANS) is an early pathological feature of HD by quantitatively characterizing functional connections between brain regions that regulate the ANS in children with the gene expansion that causes HD using magnetic resonance imaging (MRI). I will also investigate unique physiologic measures of ANS function and early effects on the vascular system in these participants. ANS dysfunction has been described in adult patients with HD, but it has been thought that this is a secondary complication of neurodegeneration. However, I recently discovered that children carrying the HD gene expansion that causes HD (GE children) exhibit symptoms consistent with enhanced sympathetic tone decades prior to their predicted motor onset. These findings indicate that ANS dysfunction may be one of the earliest manifestations of neurodegeneration in HD. As a result, the ANS may be a therapeutic target for disease modification of HD, but more information is required. The ANS is highly regulated by cortical brain regions that comprise the Central Autonomic Network (CAN), and cortical thinning and atrophy have been well-described in HD. However, there are no published reports that have objectively characterized the integrity of the functional connections in the CAN in HD. I will perform resting-state and tasked functional MRI on GE children to characterize the function of the CAN at different stages of the disease. This experiment will test the specific hypothesis that quantitative changes in functional integrity of the CAN are apparent decades prior to the predicted motor onset of HD. Additionally, I will explore physiologic measure of ANS dysfunction including baroreflex sensitivity (BRS) and how this relates to the function of the vascular system early in the disease course of HD. Specifically, I will measure aortic stiffness and carotid artery compliance while also measuring cerebral blood flow using arterial spin labeling to test the hypotheses that relative to healthy control children, GE children will demonstrate increased aortic stiffness, decreased BRS, and decreased cerebral blood flow. These experiments will provide vital information regarding when ANS dysfunction occurs in HD, the underlying mechanisms causing the dysfunction, and if these changes have negative effects on the cardiovascular system early in the disease course. I have a unique background that positions me well to be a successful translational scientist. Further training is required in sophisticated neuroimaging methods, neurodevelopment and neurobiology, as well as biostatistics. The proposed integrated research, world-class mentorship team, and didactic training programs will ensure my short-term and long-term success. Additionally, the proposed research and training plans support my long-term career goal to be an independent translational pharmacist studying the structure and function of the brain in patients with HD to advance therapeutic strategies.

项目概要/摘要这个以患者为导向的职业发展奖（K23）的目的是支持我的短期确定自主神经系统（ANS）功能障碍是否是一种早期病理学的职业目标 HD 的特征是通过定量表征调节大脑区域之间的功能连接使用磁共振成像 (MRI) 对患有导致 HD 基因扩展的儿童进行 ANS 治疗。我也会研究 ANS 功能的独特生理测量以及这些患者对血管系统的早期影响参与者。成人 HD 患者中已有 ANS 功能障碍的描述，但人们认为这是神经退行性变的继发并发症。然而，我最近发现携带高清的孩子导致 HD 的基因扩增（GE 儿童）表现出与交感神经张力增强一致的症状比他们预测的运动开始早了几十年。这些发现表明 ANS 功能障碍可能是其中之一 HD 中神经变性的最早表现。因此，ANS 可能成为疾病的治疗靶点修改HD，但需要更多信息。 ANS 受到大脑皮层区域的高度调节，包括中央自主网络（CAN），皮质变薄和萎缩已在高清。然而，尚无已发表的报告客观地描述了功能的完整性。 CAN 中的高清连接。我将对 GE 儿童进行静息态和任务功能 MRI 描述 CAN 在疾病不同阶段的功能。本实验将测试具体假设 CAN 功能完整性的定量变化早于预测的几十年就已明显出现 HD 运动发作。此外，我将探索 ANS 功能障碍的生理测量，包括压力反射敏感性 (BRS) 及其与 HD 病程早期血管系统功能的关系。具体来说，我将测量主动脉硬度和颈动脉顺应性，同时还测量脑血使用动脉自旋标记来测试以下假设：相对于健康对照儿童，GE 儿童将表现出主动脉僵硬度增加、BRS 降低和脑血流量减少。这些实验将提供有关 HD 中 ANS 功能障碍何时发生、潜在机制的重要信息导致功能障碍，以及这些变化是否早期对心血管系统产生负面影响在病程中。我拥有独特的背景，使我能够成为一名成功的翻译人员科学家。需要在复杂的神经影像方法、神经发育和神经生物学，以及生物统计学。拟议的综合研究、世界一流的指导团队以及教学培训计划将确保我短期和长期的成功。此外，拟议的研究和培训计划支持我的长期职业目标，成为一名独立的转化药剂师，研究 HD 患者大脑的结构和功能，以推进治疗策略。