Early life bladder inflammatory events in female mice lead to subsequent LUTS in adulthood

雌性小鼠生命早期的膀胱炎症事件导致成年后的 LUTS

• 批准号: 10638866
• 负责人: Stephen Anthony Zderic
• 金额: $ 61.08万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638866
• 关键词: Acrolein; Acute; Address; Adult; Age; Anxiety; Astrocytes; Basic Science; Behavior; Bladder; Bladder Dysfunction; Brain; Brain region; Catheters; Cell Nucleus; Cells; Clinical; Clinical Research; Communication; Conscious; Cyclophosphamide; Cystitis; Data; Elderly; Encephalitis; Esthesia; Etiology; Event; Female; Frequencies; Functional disorder; Future; Hippocampus; IL18 gene; Inflammasome; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Intervention; Lead; Life; Link; Longevity; Low Prevalence; Macrophage; Maps; Mental Depression; Microglia; Modeling; Mus; Neonatal; Neurons; Obstruction; Pathway interactions; Patients; Phenotype; Prosencephalon; Quality of life; Recurrence; Regulation; Reporting; Research; Rodent; Role; Sensory; Signal Transduction; Specificity; Testing; Therapeutic; Time; Urinary tract infection; Urination; Urologist; anxiety-like behavior; brain dysfunction; care costs; comorbidity; cytokine; early childhood; experience; experimental study; frontal lobe; in vivo monitoring; indexing; insight; locus ceruleus structure; lower urinary tract symptoms; male; mouse model; novel therapeutics; optogenetics; pharmacologic; postnatal; psychologic; reduce symptoms; tool

PROJECT SUMMARY Lower Urinary Tract Symptoms (LUTS) are among the most common reasons to see a urologist across the lifespan and are often accompanied by psychological consequences, such as anxiety and depression. Patients with LUTS may have a disrupted bladder–brain dialogue; they may say “I don’t even feel anything until I am wet”. Better therapeutic options can emerge from a better understanding of the fundamental brain circuits and cells that contribute to LUTS and that contribute to bladder–brain communication. A potential LUTS etiology that merits closer study is early life urinary tract infection (UTI). Clinical studies in females (who have UTIs 4x more often than males) show early life UTIs predict later life LUTS. Basic research on UTIs and other bladder insults in adulthood suggest inflammation underlies acute LUTS and psychological consequences. For example, adult systemic injection of cyclophosphamide (CYP) — the most common noninvasive (catheter-free) way to model UTI-linked inflammation — leads to bladder and psychobehavioral dysfunction. However, there is a striking absence of research on the role of early life UTIs in later life LUTS and psychological consequences. Here we show for the first time that female mice experiencing repeated, early life cystitis after CYP have bladder and psychobehavioral dysfunction in adulthood. These data fuel our hypotheses: Early life CYP-induced cystitis induces bladder and brain inflammation, which disrupts bladder-brain dialogue and leads to lifelong LUTS and psychobehavioral consequences; this later life bladder and brain dysfunction can be reversed by manipulation of key brain circuits in adulthood. In Aim 1, we will define early life CYP-induced inflammatory indices in bladder and brain across the lifespan. In Aim 2, we will determine early-life CYP-induced functional changes in bladder and brain across the lifespan, launching off from our pilot data: repeated, early-life CYP-induced cystitis leads to adulthood voiding dysfunction and anxiety-like behavior. We will use pharmacologic tools to address the mechanism and specificity of these functional changes, and test for anxiety- and depression-like phenotypes throughout life. In Aim 3, we will map and manipulate key components of the brain circuits that contribute to bladder-brain dialogue. Using our proven abilities to assess neuron activity in brain regions central to this dialogue (locus coeruleus, Barrington’s nucleus, frontal cortex), we will record the activity of sets of neurons in freely-moving mice before and after voiding events in our early life CYP model. We hypothesize that early life cystitis disrupts the ability of these neuron types to respond to sensation from the bladder and thus discriminate voiding cycle stages. We will then attempt to reverse the early life cystitis-induced bladder and psychobehavioral dysfunction in later life by optogenetically manipulating the activity of relevant neurons in adulthood, as we have already done in adult models. Given the prevalence of LUTS, the basic experiments proposed here have enormous potential to expand our understanding of how neonatal cystitis influences the bladder-brain dialogue throughout the lifespan.

项目摘要 较低的尿路症状（LUTS）是看到整个泌尿科医生的最常见原因之一 寿命，通常伴随着心理后果，例如焦虑和抑郁。 LUTS患者可能会受到膀胱脑对话的干扰；他们可能会说：“我什至什么都没有 直到我被湿之前”。从更好地理解基本大脑会出现更好的治疗选择 导致LUTS并导致膀胱脑通信的电路和细胞。潜在的LUTS 值得仔细研究的病因是早期尿路感染（UTI）。女性的临床研究（有 比男性比男性更频繁地表现出早期的生活，预测了以后的生活。关于UTI和其他的基础研究 成年中的膀胱侮辱表明，感染是急性LUT和心理后果的基础。为了 例如，成人全身注射环磷酰胺（CYP） - 最常见的无创（无导管） 建模与UTI相关的注射的方法 - 导致膀胱和心理功能障碍。但是，有 关于早期尿道在以后的生活中的作用和心理后果的作用的显着研究。 在这里，我们首次表明雌性小鼠反复经历，CYP之后的早期膀胱炎 成年后的膀胱和心理功能障碍。这些数据推动了我们的假设：早期生活 CYP诱导的膀胱炎会影响膀胱和脑感染，这破坏了膀胱脑对话和铅 终身情绪和心理狂热后果；以后的生活膀胱和大脑功能障碍可能是 在成年期间操纵关键的大脑电路而逆转。在AIM 1中，我们将定义早期生活CYP引起的 整个寿命中的膀胱和大脑的炎症指标。在AIM 2中，我们将确定早期生活 CYP引起的整个寿命中膀胱和大脑的功能变化，从我们的试验数据中启动： 重复的早期CYP诱导的膀胱炎导致成人功能障碍和动画样行为。我们 将使用药品工具来解决这些功能更改的机制和特异性，并测试 一生中的焦虑和抑郁型表型。在AIM 3中，我们将映射并操纵密钥 大脑电路的组成部分有助于膀胱脑对话。利用我们验证的能力来评估 大脑区域的神经元活动中心的对话中心（位点coeruleus，Barrington的核us，额叶皮层）， 我们将记录在早期无效事件之前和之后的自由移动小鼠中的神经元的活动 Life CYP模型。我们假设早期膀胱炎破坏了这些神经元类型的反应能力 膀胱的感觉，因此区分了空隙周期阶段。然后，我们将尝试扭转 早期膀胱炎引起的膀胱和精神病性功能障碍在后来的生活中通过吻合式操纵 正如我们在成人模型中所做的那样，相关神经元的活性。考虑到流行 LUTS，这里提出的基本实验具有巨大的潜力，可以扩展我们对 新生儿膀胱炎影响整个生命周期的膀胱脑对话。