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:
    10212681
  • 负责人:
  • 金额:
    $ 18.05万
  • 依托单位:
  • 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

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.
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.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jordan Schultz其他文献

Jordan Schultz的其他文献

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{{ truncateString('Jordan Schultz', 18)}}的其他基金

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:
    10360540
  • 财政年份:
    2021
  • 资助金额:
    $ 18.05万
  • 项目类别:
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:
    10620644
  • 财政年份:
    2021
  • 资助金额:
    $ 18.05万
  • 项目类别:
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