MACROPHAGE MIR146B AND OCULAR NEOVASCULARIZATION

巨噬细胞 MIR146B 和眼新生血管化

• 批准号: 10285203
• 负责人: RAJENDRA S APTE
• 金额: $ 39.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285203
• 关键词: Affect; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Applications Grants; Behavior; Blindness; Bone Marrow; Brain; CCL2 gene; Cells; Cerebrum; Data; Defense Mechanisms; Dementia; Deposition; Development; Disease; Disease Progression; Elderly; Epidemic; Exhibits; Eye; Eye diseases; Genes; Homeostasis; Immune; Immune system; Immunologic Surveillance; In Vitro; Inflammaging; Inflammation; Inflammatory; Interleukin-1 beta; Knockout Mice; Laboratories; Link; Macrophage Activation; Mediating; MicroRNAs; Microglia; Molecular; Molecular Target; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Pattern; Phagocytes; Phagocytosis; Phenotype; Play; Process; Research; Retina; Role; Sentinel; Time; Tissues; Transplantation; United States National Institutes of Health; Untranslated RNA; abeta accumulation; age related; aged; chemokine; conditional knockout; cytokine; efficacy evaluation; insight; macrophage; metabolic fitness; monocyte; mouse model; neovascularization; neuroinflammation; neurotoxic; ocular neovascularization; overexpression; parent grant; recruit; repaired; response; sensor; transcriptomics; β-amyloid burden

Macrophages are innate immune cells that are critically important as immune sensors and sentinels in homeostasis. They also play pivotal roles in the development of age-induced diseases through their contribution to repair and para-inflammation within tissues. Identifying the regulators that determine macrophage behavior has tremendous potential for altering the course of diseases such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). With age, macrophages exhibit a pro-inflammatory phenotype characterized by aberrant activation and altered polarization. This macrophage phenotype is often called ‘inflammaging’. Our laboratory has demonstrated that the inability of aged macrophages to regulate inflammation and pathologic angiogenesis in the eye leads to proliferative neovascularization and neurodegeneration, causes of catastrophic vision loss in AMD. In the brain, as in the eye, resident macrophages called microglia are tasked with the crucial role of phagocytosis and clearance of neurotoxic molecules during immunosurveillance. However, this natural defense mechanism is diminished with aging and is especially deficient in neurodegenerative diseases such as AD, that cause dementia. Although the role of microglia in AD has been extensively studied, the contributions of bone-marrow derived macrophages (BMDMs) to CNS homeostasis in the context of aging and neurodegeneration is still limited. While in the healthy brain microglia operate as the dominant immune cells that maintain CNS homeostasis, in the setting of age-associated para-inflammation and neurodegenerative diseases such as AD, BMDMs are mobilized to the brain. Interestingly, BMDMs show a higher phagocytic clearance of cerebral amyloid deposits than microglia and recruitment of BMDMs into the brain has been demonstrated to significantly impact Amyloid beta (Aß) burden in AD models. In an unbiased transcriptomic analysis, we recently identified macrophage miR146b as a ‘non-coding’ microRNA (miR) that was significantly altered during aging. miR146b progressively declined with increasing age across all time points examined in a robust pattern that was not seen with any other miR. Age-related and antagomir-mediated reduction in miR146b led to decreased expression of IL1ß and CCL2, cytokines/chemokines critical in recruiting circulating monocytes into the CNS in response to Aß accumulation. These data suggest that miR146b may be a ‘master regulator’ of macrophage aging and a key molecule in the molecular pathogenesis of AD progression. Although the link between neuro-inflammation and AD pathology is now well recognized, how the age-related molecular and functional changes in BMDMs contribute to AD disease progression warrants further elucidation. In this grant application, we propose to examine how the miR146b-regulated aging process in macrophages alters their response to Aß and impacts AD-associated processes in the following specific aims: Aim 1) Determine the impact of macrophage miR146b expression on Alzheimer’s disease. To demonstrate that altered macrophage miR146b expression plays an important role in AD pathology, we will a) utilize macrophage- specific miR146b conditional knockout mice (mir146bcko) to demonstrate that loss of miR146b exacerbates disease progression and b) evaluate the efficacy of transplanting miR-146b- overexpressing BMDM in suppressing Aß pathology in 5xFAD mice model of AD. Aim 2) Elucidate the differential molecular and cellular responses of miR146b null and wildtype macrophages to Aß and define their functional significance. We will perform in vitro characterization of a) the impact of miR146b and b) its putative target genes on the activation status, phagocytic capacity and metabolic fitness of BMDM derived from wild type or mir146bcko mice. These studies will demonstrate the pathologic consequences (Aim 1) of altered miR146b expression in macrophages on AD progression and identify the mechanisms (Aim 2) that affect macrophage behavior in response to AD pathology. This targeted molecular approach will offer new insight into the contribution of age-induced molecular changes in macrophages that influence AD pathogenesis. These results will also form the basis of comprehensive grant applications for additional studies into AD pathogenesis. This proposed research is within the scope of the parent grant (NIH R01 EY 019287). The focus of the parent grant is on the effect of macrophage miR146b in age-related macular degeneration (AMD), a blinding eye disease characterized by retinal neurodegeneration and loss of vision. Macrophages are important inflammatory cells that regulate pathogenesis of both AMD and AD, diseases of aging that have reached epidemic proportions. Understanding whether macrophage miR146b regulates neurodegeneration in AD will enhance our understanding of macrophage inflammation in aging and diseases characterized by neurodegeneration in the elderly.

巨噬细胞是先天性免疫细胞，在免疫系统中作为免疫传感器和哨兵至关重要

项目成果

Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.

• DOI: 10.1128/mbio.00925-23
• 发表时间: 2023-08-31
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Lin, Joseph B.;Mora, Amy;Wang, Tzu Jui;Santeford, Andrea;Usmani, Darksha;Ligon, Marianne M.;Mysorekar, Indira U.;Apte, Rajendra S.
• 通讯作者: Apte, Rajendra S.

Sourcing Photoreceptor-like Cells for Treating Vision Loss.

• DOI: 10.1056/nejmcibr2027602
• 发表时间: 2020-11-05
• 期刊: NEW ENGLAND JOURNAL OF MEDICINE
• 影响因子: 158.5
• 作者: Apte, Rajendra S.

Vitreous microparticles contain apoptotic signals suggesting a diabetic vitreopathy.

• DOI: 10.18240/ijo.2022.01.14
• 发表时间: 2022-01
• 期刊: International journal of ophthalmology
• 影响因子: 1.4
• 作者: Harris Sultan;R. Rajagopal;P. Rao;Kisha Piggott;Michael A. Paley;L. Hassman;A. S. Li;B. Marshall;R. Apte

Association of Systemic Lupus Erythematosus Disease Activity With Choroidal Thickness.

系统性红斑狼疮疾病活动与脉络膜厚度的关联。

• DOI: 10.1097/rhu.0000000000002036
• 发表时间: 2024
• 期刊: Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases
• 作者: Lee,Iris;Gomez,AndreaRamirez;Kim,AlfredHJ;Coble,DeanW;Marshall,Brigid;Shah,Aaditya;Eisen,Seth;Apte,RajendraS;Li,Tingting
• 通讯作者: Li,Tingting