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

项目摘要/摘要 老年性血管性认知障碍和痴呆(VCID)是阿尔茨海默病及其相关疾病的一个亚型 痴呆症是老年人残疾和生活质量下降的常见原因。广泛的近期 数据表明，大脑中的微血管病变在这些过程中发挥着核心作用。这样的一个 病理是脑微出血(CMH)，这是脑内小血管破裂的结果 并逐渐损害神经功能。CMH的发病率随着年龄和高血压的增加而显著增加。 是年龄相关性认知功能下降的主要原因之一。然而，CMH和CMH的潜在细胞机制 血管脆弱性的增加是未知的，因此没有治疗干预措施来缓解CMH。血样 血管的完整性需要血管平滑肌细胞(VSMCs)的可塑性，VSMCs表现出从 高度收缩，以保护性、抗脆性表型应对压力。老龄化从根本上改变了VSMC 表型交换，抑制采用这些保护性VSMC特征，否则会促进这些特征的采用 通过胰岛素样生长因子(IGF)-1。随着年龄的增长，循环中的IGF-1水平显著降低。低水平的IGF-1 在我们的啮齿动物模型中，增加脑微血管疾病的风险，促进CMH的发展， 支持胰岛素样生长因子-1缺乏在年龄相关的血管脆弱性中的作用。我们的假设是受损的VSMC IGF-1缺乏导致的可塑性和功能在增加脑血管脆性和 CMH的发生与认知功能随年龄增长而下降。目标1将检验以下假设：VSMC对 IGF-1信号缺陷模型中VCID/ADRD表型的发展。我们将使用新型的VSMC特定的IGF- 1受体基因敲除系探讨VSMCs在CMH发生、肌源性自身调节受损中的作用 对高血压的反应，以及随之而来的认知能力下降。目标2将决定 不适应表型VSMCs与保护性表型VSMC的动态平衡 IGF1呈年龄依赖性下降。在这个目标中，我们将解决VSMC在体内的可塑性问题， 评估Igf1r缺乏性CMH患者脑血管VSMC的保护性和适应性不良表型 模特们。AIM 3将评估调节适应不良和保护性VSMC的转录机制 血管脆性/CMH区域和周围完整血管的表型。谱系追踪遗传小鼠 衰老和IGF-1缺乏的模型，结合单细胞RNA测序，将被用来评估 新的转录调节因子在采用不同的VSMC表型中的作用。支持和反脆弱性的VSMC 表型状态将在空间上与CMH的位置重叠，以检验CMH发生的假设 主要是在VSMC表现出不适应表型的地区。这些科学和技术上的创新 研究将显著提高我们对IGF-1缺乏在CMH发生中的作用的理解 并将提供对有效发展的关键的潜在细胞机制的洞察 治疗。

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.