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

• 批准号: 10212681
• 负责人: Jordan Schultz
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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/10212681
• 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; Spin Labels; Structure; Sympathetic Nerve Block; Sympathetic Nervous System; Symptoms; Testing; Therapeutic; Thinness; Time; Training; Training Programs; Trinucleotide Repeats; Vascular System; aged; 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

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.

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.