CNS Mechanisms of IC/BPS

IC/BPS 的 CNS 机制

基本信息

批准号：
10659829
负责人：
Robert W Gereau
金额：
$ 66.4万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659829
关键词：
Abdomen Affect Affective Amygdaloid structure Analgesics Anatomy Animals Anxiety Behavior Bladder Brain Cell Nucleus Central Lateral Nucleus Central Medial Thalamic Nucleus Chronic Clinical Cyclophosphamide Cystitis Development Disease Etiology Functional Imaging Functional disorder Funding Genetic Hyperalgesia Hypersensitivity In Situ Hybridization Incidence Increased frequency of micturition Injury Interstitial Cystitis Label Lead Maintenance Maps Mediating Mental Depression Modeling Mood Disorders Mus Neurons Neurosciences Nociception Nociceptors Output Pain Patch-Clamp Techniques Pathologic Pathology Patients Persistent pain Physiology Play Population Prevalence Process Property Quality of life Regulation Reporting Resolution Rodent Role Series Slice Symptoms System Testing United States Woman Work antinociception bladder pain central sensitization comorbidity design effective therapy generalized anxiety imaging study in vivo insight micturition urgency mouse model negative affect neural circuit neuronal circuitry pharmacologic pre-clinical response segregation sensory stimulus single nucleus RNA-sequencing transcriptomics

项目摘要

Abstract Interstitial cystitis/Bladder Pain Syndrome (IC/BPS) is a serious and painful condition of unknown etiology that affects 6% of women in the United States. The major clinical symptoms of IC/BPS are pain on bladder filling and increased urinary urgency and frequency. The majority of IC/BPS patients (90%) also suffer from comorbid anxiety and/or depression, contributing to a poor quality of life. Current available treatments for IC/BPS are largely ineffective, providing only mild symptomatic relief. Given the prevalence of this debilitating disease and the lack of effective treatments, further studies are needed to better understand the underlying mechanisms that contribute IC/BPS and those that mediate the high incidence of comorbid anxiety and depression. We previously reported that IC/BPS patients show referred abdominal hyperalgesia, a clear sign of central sensitization. In the previous funding period, we used the single nucleus RNA sequencing, spatial transcriptomics and in situ hybridization and identified two populations of CeA neurons that are activated in cystitis and appear to play opposing roles in the regulation of bladder pain. Here we will apply state of the art approaches in systems neuroscience to unravel the potential role of these unique neuronal subpopulations in the CeA in the reciprocal regulation of pain, voiding dysfunction, and negative affective behaviors (IC/BPS-like conditions). What are the respective roles of the two populations in bladder pain? Are the apparent pro- and anti-nociceptive actions of the Pde1c and Cartpt populations, respectively, restricted to referred hypersensitivity, or do they also reciprocally regulate ongoing pain? Do these populations play differential roles in the regulation of voiding behavior and negative affective behaviors? What are the critical inputs to and projections from these neurons? Do these populations undergo plasticity differentially in the induction and maintenance of cystitis? How do the dynamics of this circuit change as cystitis resolves? Here we propose to answer these questions in a series of studies that test the central hypothesis that maladaptive plasticity in these unique subpopulations of CeA neurons regulates voiding dysfunction, pain sensitization, and comorbid negative affect in models of cystitis. These studies will provide new insights into the critical role of the pro- and anti-nociceptive neurons in the CeA in bladder pain and comorbid affective disorders in the context of bladder pain syndrome. If successful, these studies will point the way to identifying pharmacological approaches to restore normal circuit function around these neurons to provide relief from bladder pain, voiding dysfunction, and comorbid anxiety and depression in patients with IC/BPS.

抽象的间质性膀胱炎/膀胱疼痛综合征 (IC/BPS) 是一种病因不明的严重且痛苦的疾病，影响美国 6% 的女性。 IC/BPS 的主要临床症状是膀胱充盈疼痛和尿急和尿频增加。大多数 IC/BPS 患者 (90%) 还患有合并症焦虑和/或抑郁，导致生活质量差。目前可用的 IC/BPS 治疗方法有基本上无效，仅提供轻微的症状缓解。鉴于这种使人衰弱的疾病的流行和由于缺乏有效的治疗方法，需要进一步研究以更好地了解其潜在机制贡献 IC/BPS 以及介导共病焦虑和抑郁高发生率的因素。我们之前据报道，IC/BPS 患者表现出腹部痛觉过敏，这是中枢敏化的明显迹象。在在之前的资助期间，我们使用了单核RNA测序、空间转录组学和原位杂交并鉴定出两组在膀胱炎中被激活并似乎发挥作用的 CeA 神经元在膀胱疼痛的调节中发挥相反的作用。在这里，我们将在系统中应用最先进的方法神经科学揭示了 CeA 中这些独特的神经元亚群在交互作用中的潜在作用疼痛、排尿功能障碍和消极情感行为（IC/BPS 样病症）的调节。有哪些两个人群在膀胱疼痛中各自的作用？是否有明显的促伤害和抗伤害行为？ Pde1c 和 Cartpt 人群分别仅限于所涉及的超敏反应，或者它们也相互影响调节持续的疼痛？这些人群在排尿行为的调节中是否发挥着不同的作用？负面情感行为？这些神经元的关键输入和投射是什么？做这些人群在膀胱炎的诱发和维持方面经历可塑性差异？动态如何当膀胱炎消退时，该回路会发生变化吗？在这里，我们建议通过一系列研究来回答这些问题检验中心假设，即这些独特的 CeA 神经元亚群中的适应不良可塑性调节膀胱炎模型中的排尿功能障碍、疼痛敏感性和共病负面影响。这些研究将为了解 CeA 中促伤害感受神经元和抗伤害感受神经元在膀胱疼痛和膀胱疼痛综合征背景下的共病情感障碍。如果成功的话，这些研究将指出确定恢复这些神经元周围正常回路功能的药理学方法的方法，以提供缓解 IC/BPS 患者的膀胱疼痛、排尿功能障碍以及共病焦虑和抑郁。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala.

中央杏仁核瘙痒调节的细胞、回路和转录框架。

DOI：
发表时间：
2021
期刊：
影响因子：
7.7
作者：
Samineni, Vijay K;Grajales;Grajales;Tycksen, Eric;Copits, Bryan A;Pedersen, Christian;Ankudey, Edem S;Sackey, Julian N;Sewell, Sienna B;Bruchas, Michael R;Gereau, Robert W
通讯作者：
Gereau, Robert W

Wireless, Battery-Free Implants for Electrochemical Catecholamine Sensing and Optogenetic Stimulation.

用于电化学儿茶酚胺传感和光遗传学刺激的无线、无电池植入物。

DOI：
10.1021/acsnano.2c09475
发表时间：
2022-12-22
期刊：
ACS nano
影响因子：
17.1
作者：
Tucker Stuart;W. Jeang;Richard A. Slivicki;Bobbie J. Brown;Alex Burton;Victoria E. Brings;Lilian C Alarcón;Prophecy Agyare;Savanna Ruiz;Am;a Tyree;a;Lindsay Pruitt;S. Madhvapathy;Martin J. Niemiec;James Zhuang;Siddharth R. Krishnan;B. Copits;J. A. Rogers;R. Gereau;V. Samineni;A. B;odkar;odkar;P. Gutruf
通讯作者：
P. Gutruf

Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray.

导水管周围灰质瘙痒感觉和情感成分的细胞类型特异性调节。