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.

项目总结/文摘