IGF-1, smooth muscle plasticity, and pathogenesis of cerebral microhemorrhages in aging

IGF-1、平滑肌可塑性与衰老脑微出血的发病机制

• 批准号: 10077915
• 负责人: Shannon M Conley
• 金额: $ 29.19万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077915
• 关键词: Adopted; Adoption; Affect; Age; Age-associated memory impairment; Aged, 80 and over; Aging; Apoptosis; Area; Biological; Blood Vessels; Brain; Caliber; Cell Lineage; Cells; Cellular biology; Cerebrum; Characteristics; Cognitive; Cognitive deficits; Complex; Coupled; Data; Defect; Development; Disease; Elderly; Environment; Evaluation; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Space; Gait; Gait abnormality; Genetic; Genetic Transcription; Geroscience; Goals; Growth; Growth Factor; Heterogeneity; Homeostasis; Hyperplasia; Hypertension; Hypertrophy; Impaired cognition; Impairment; Incidence; Individual; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Link; Location; Mechanical Stress; Mediating; Molecular; Mus; Muscle Development; Nature; Neurologic; Neurons; Oxidative Stress; Pathogenesis; Pathway interactions; Phenotype; Population; Positioning Attribute; Quality of life; Regulation; Risk; Rodent Model; Role; Rupture; Severities; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stress; Stretching; Structure; Supplementation; Testing; Therapeutic Intervention; Vascular Smooth Muscle; age related; aged; base; cell age; cerebral artery; cerebral microbleeds; cerebrovascular; effective therapy; experience; experimental study; hemodynamics; improved; in vivo; innovation; insight; knock-down; knockout animal; laser capture microdissection; mouse model; novel; pressure; response; single-cell RNA sequencing; stressor; therapeutic candidate; transcription factor; Adopted; Adoption; Affect; Age; Age-associated memory impairment; Aged, 80 and over; Aging; Apoptosis; Area; Biological; Blood Vessels; Brain; Caliber; Cell Lineage; Cells; Cellular biology; Cerebrum; Characteristics; Cognitive; Cognitive deficits; Complex; Coupled; Data; Defect; Development; Disease; Elderly; Environment; Evaluation; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Space; Gait; Gait abnormality; Genetic; Genetic Transcription; Geroscience; Goals; Growth; Growth Factor; Heterogeneity; Homeostasis; Hyperplasia; Hypertension; Hypertrophy; Impaired cognition; Impairment; Incidence; Individual; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Link; Location; Mechanical Stress; Mediating; Molecular; Mus; Muscle Development; Nature; Neurologic; Neurons; Oxidative Stress; Pathogenesis; Pathway interactions; Phenotype; Population; Positioning Attribute; Quality of life; Regulation; Risk; Rodent Model; Role; Rupture; Severities; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stress; Stretching; Structure; Supplementation; Testing; Therapeutic Intervention; Vascular Smooth Muscle; age related; aged; base; cell age; cerebral artery; cerebral microbleeds; cerebrovascular; effective therapy; experience; experimental study; hemodynamics; improved; in vivo; innovation; insight; knock-down; knockout animal; laser capture microdissection; mouse model; novel; pressure; response; single-cell RNA sequencing; stressor; therapeutic candidate; transcription factor

PROJECT SUMMARY/ABSTRACT Cerebral microhemorrhages (CMH) result from rupture of small intracerebral blood vessels and progressively impair neuronal function. The incidence of CMH dramatically increases with age and hypertension and is a major cause for age-related cognitive decline. Cognitive decline caused by CMH has severe impacts on quality-of-life, yet remains untreatable. CMHs occur due to increased vascular fragility but underlying mechanisms are unknown, and thus therapeutic interventions to mitigate CMHs are not available. Blood vessel integrity requires plasticity of vascu- lar smooth muscle cells (VSMCs), which exhibit an adaptive switch from a highly contractile to a protective anti- fragility phenotype in response to stress. Aging fundamentally alters VSMC phenotypic switching, suppressing the adoption of this protective VSMC phenotype. In contrast, insulin-like growth factor (IGF)-1 has vasoprotective ef- fects and promotes adoption of the protective anti-fragility phenotype, but circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels increase the risk for cerebromicrovascular disease and promote the devel- opment of CMH in our rodent models, supporting a role for IGF-1 deficiency in age-related vascular fragility. Our hypothesis is that impaired VSMC phenotypic switching due to IGF-1 deficiency has a fundamental role in in- creased cerebrovascular fragility and development of CMH with age. Aim 1 will test the hypothesis that in- creased CMH in aging is due to vascular fragility arising from decreased IGF-1 signaling in VSMCs. Development of CMH, associated neurological/gait defects, and VSMC phenotype will be compared in mice with VSMC-specific disruption of IGF-1 signaling, mice with overall disruption of IGF-1 signaling, and aged mice coupled with IGF-1 supplementation/rescue. Aim 2 will use cultured aged, young, and IGF-1 receptor knockdown VSMCs to test the hypothesis that IGF-1 signaling is required for VSMC cellular adaptation to hemodynamic stress and will eval- uate novel mechanisms mediated by the transcription factors Tbx15/18 for this regulation. Aim 3 will test the hypothesis that VSMC phenotypic heterogeneity influences the development of CMH. VSMCs exist in a heter- ogeneous pool in which multiple phenotypes co-exist, determined based on growth factors including IGF-1 and other stimuli in the extracellular space, but the characteristics of this heterogeneity in cerebral arteries is un- known. VSMC lineage tracing genetic mouse models of aging and IGF-1 deficiency, coupled with single-cell RNA-sequencing will be used to characterize VSMC heterogeneity. Newly discovered pro- and anti-fragility VSMC phenotypic states will be correlated with location of CMH bleeds to test the hypothesis that CMHs occur primarily in regions where VSMCs show a maladaptive phenotype The scientifically and technically innovative studies proposed here will significantly enhance our understanding of the role of IGF-1 deficiency in the devel- opment of CMH and will provide critical insight into cellular mechanisms underlying it, both of which are critical for the development of effective therapies.

项目摘要/摘要 小脑血管破裂并逐渐受损 神经元功能。 CMH的发生率大大增加了随着年龄和高血压的增长，这是一个主要原因 与年龄有关的认知下降。由CMH引起的认知下降对生活质量有严重影响 保持不可治疗。 CMHS发生是由于血管脆弱性增加而导致的，但潜在的机制尚不清楚，并且 因此，无法提供减轻CMH的治疗干预措施。血管的完整性需要Vascu的可塑性 Lar平滑肌细胞（VSMC），其自适应切换从高度收缩到保护性抗 响应压力的脆弱表型。老化从根本上改变了VSMC表型转换，抑制了 采用这种保护性VSMC表型。相反，胰岛素样生长因子（IGF）-1具有血管保护EF- 纤维和促进保护性抗肿瘤表型的采用，但是循环的IGF-1水平急剧 随着年龄的增长而下降。低IGF-1水平会增加脑血管疾病的风险，并促进Devel- 在我们的啮齿动物模型中，CMH的操作支持IGF-1缺乏在与年龄相关的血管脆性中的作用。我们的 假设是，由于IGF-1缺乏症而导致的VSMC表型转换受损 随着年龄的增长，CMH的脑血管脆弱性和发育。 AIM 1将检验以下假设。 衰老中的CMH折痕是由于VSMC中IGF-1信号传导降低引起的血管脆弱性。发展 在具有VSMC特异性的小鼠中，将比较CMH，相关的神经/步态缺陷和VSMC表型 IGF-1信号传导的破坏，IGF-1信号总体破坏的小鼠以及与IGF-1相连的老年小鼠 补充/救援。 AIM 2将使用培养的老化，年轻和IGF-1受体敲低VSMC测试 VSMC细胞适应血液动力学胁迫需要IGF-1信号传导的假设，并将评估 对于该调节，由转录因子TBX15/18介导的新型机制。 AIM 3将测试 VSMC表型异质性影响CMH的发展的假设。 VSMC存在于异性 不可证明的池，其中多种表型共存，基于生长因子，包括IGF-1和 细胞外空间中的其他刺激，但是这种异质性在脑动脉中的特征是 已知。 VSMC谱系追踪衰老和IGF-1缺乏症的遗传小鼠模型，并与单细胞结合 RNA-sequencing将用于表征VSMC异质性。新发现的亲和抗差异 VSMC表型状态将与CMH出血的位置相关，以检验CMHS发生的假设 主要在VSMC显示不良适应性表型的地区，科学和技术创新 这里提出的研究将显着增强我们对IGF-1缺乏在Devel-devel-的作用的理解。 CMH的操作将对其基础的细胞机制提供关键的见解，这两者都是至关重要的 用于开发有效的疗法。