The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia

血管平滑肌细胞中 IGF-1 信号传导在年龄相关血管认知障碍和痴呆中的作用

• 批准号: 10489846
• 负责人: Shannon M Conley
• 金额: $ 35.71万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10489846
• 关键词: Address; Adoption; Affect; Age; Age-Years; Age-associated memory impairment; Aging; Alzheimer' s disease related dementia; Apoptosis; Area; Behavioral; Blood Vessels; Brain; Cell Proliferation; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Characteristics; Chronology; Cognitive; Coupled; Data; Defect; Development; Disease; Elderly; Equilibrium; Event; Exhibits; Extracellular Matrix; Functional disorder; Gait abnormality; Genetic; Genetic Transcription; Geroscience; Goals; Growth; Health; Health Care Costs; Hemorrhage; Homeostasis; Human; Hyperplasia; Hypertension; Hypertrophy; IGF1 gene; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Inflammatory; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knock-out; Link; Location; Mediating; Modeling; Molecular Profiling; Neuronal Dysfunction; Neurons; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Public Health; Quality of life; Regulation; Risk; Risk Factors; Rodent Model; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Somatomedins; Stimulus; Stress; Subgroup; Testing; Therapeutic Intervention; Vascular Cognitive Impairment; Vascular Smooth Muscle; Work; age related; aged; aging brain; cell growth; cerebral microbleeds; cerebrovascular; cognitive development; cohort; disability; effective therapy; healthspan; in vivo; innovation; insight; laser capture microdissection; microvascular pathology; mouse model; neuroinflammation; novel; response; senescence; single-cell RNA sequencing; therapeutic candidate; vascular cognitive impairment and dementia

PROJECT SUMMARY/ABSTRACT Age-related vascular cognitive impairment and dementia (VCID), a subgroup of Alzheimer’s Disease and Related Dementias (ADRD) is a common cause of disability and reduced quality of life among the elderly. Extensive recent data have demonstrated that microvascular pathologies in the brain play a central role in these processes. One such pathology is cerebral microhemorrhages (CMH) which are the result of rupture of small intracerebral blood vessels and progressively impairs neuronal function. The incidence of CMH dramatically increases with age and hypertension is one of the major causes for age-related cognitive decline. Yet the underlying cellular mechanisms for CMH and increased vascular fragility are unknown, and thus therapeutic interventions to mitigate CMH are not available. Blood vessel integrity requires plasticity of vascular 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 these protective VSMC features, which are otherwise promoted by insulin-like growth factor (IGF)-1. Circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels increase the risk for cerebromicrovascular disease and promote the development of CMH in our rodent models, supporting a role for IGF-1 deficiency in age-related vascular fragility. Our hypothesis is that impaired VSMC plasticity and function due to IGF-1 deficiency has a fundamental role in increased cerebrovascular fragility and development of CMH and cognitive decline with age. Aim 1 will test the hypothesis that VSMCs contribute to the development of VCID/ADRD phenotypes in IGF-1 signaling-deficient models. We will use novel VSMC-specific IGF- 1 receptor knockout lines to probe the role of VSMCs in the development of CMH, impaired myogenic autoregulation in response to hypertension, and the consequent development of cognitive decline. Aim 2 will determine the dynamic balance between VSMCs with maladaptive phenotypes and VSMCs with protective phenotypes induced by age-dependent decrease of IGF1. In this aim we will address the question of VSMC plasticity in vivo, evaluating both protective and maladaptive VSMC phenotypes in the cerebrovasculature of Igf1r-deficient CMH models. Aim 3 will evaluate the transcriptional mechanisms governing maladaptive and protective VSMC phenotypes in regions of vascular fragility/CMH and in surrounding intact vessels. Lineage tracing genetic mouse models of aging and IGF-1 deficiency, coupled with single-cell RNA-sequencing, will be used to evaluate the role of novel transcriptional regulators in the adoption of diverse VSMC phenotypes. Pro- and anti-fragility VSMC phenotypic states will be spatially overlaid with the location of CMH to test the hypothesis that CMH occur primarily in regions where VSMCs show a maladaptive phenotype. These scientifically and technically innovative studies will significantly enhance our understanding of the role of IGF-1 deficiency in the development of CMH and will provide insight into underlying cellular mechanisms which are critical for the development of effective therapies.

项目摘要/摘要 与年龄有关的血管认知障碍和痴呆（VCID），阿尔茨海默氏病及相关的亚组 痴呆症（ADRD）是老年人残疾和生活质量降低的常见原因。广泛的最近 数据表明，大脑中的微血管病理在这些过程中起着核心作用。一个这样的 病理是脑微毛（CMH），是小脑内血管破裂的结果 并逐渐损害神经元功能。 CMH的事件随着年龄和高血压而大大增加 是与年龄相关的认知下降的主要原因之一。然而，CMH和 血管脆弱性增加是未知的，因此无法减轻CMH的热干预措施。血 血管的完整性需要血管平滑肌细胞（VSMC）的可塑性，该肌肉细胞暴露了自适应开关 响应压力，高度收缩了受保护的抗差异表型。老化从根本上改变了VSMC 表型切换，抑制了这些受保护的VSMC功能的采用，否则会促进这些特征 通过胰岛素样生长因子（IGF）-1。循环IGF-1水平随着年龄的增长而大大提高。低IGF-1水平 增加脑血管疾病的风险，并在我们的啮齿动物模型中促进CMH的发展， 支持IGF-1缺乏在与年龄有关的血管脆弱性中的作用。我们的假设是VSMC受损 由于IGF-1缺乏引起的可塑性和功能在增加脑血管脆弱性和 随着年龄的增长，CMH和认知能力下降的发展。 AIM 1将检验VSMC有助于该假设 IGF-1信号缺陷模型中VCID/ADRD表型的开发。我们将使用新颖的VSMC特异性IGF- 1个受体基因敲除线以探测VSMC在CMH发展中的作用，造成肌源性自动调节受损 响应高血压以及随之而来的认知下降。 AIM 2将确定 具有不良适应性表型的VSMC与具有保护表型的VSMC之间的动态平衡 根据年龄依赖性IGF1的下降。在此目标中，我们将解决VIVO中VSMC可塑性的问题， 评估IGF1R缺乏CMH的脑血管造型的受保护和不良适应性VSMC表型 AIM 3将评估控制不良适应和受保护的VSMC的转录机制 血管脆性/CMH和周围完整vissels的区域中的表型。谱系追踪遗传小鼠 衰老和IGF-1缺乏症的模型，再加上单细胞RNA测序，将用于评估 新型转录调节剂在采用潜水员VSMC表型中的作用。利比利亚和抗差异VSMC 表型状态将与CMH的位置在空间上覆盖，以检验CMH发生的假设 首先在VSMC显示不良适应性表型的地区。这些科学和技术创新 研究将显着增强我们对IGF-1缺乏在CMH发展中的作用的理解 并将提供有关潜在的细胞机制的见解，这对于开发有效至关重要 疗法。