Regulation of Mesenchymal Stem Cell Secretome for Treatment of Microglia Damage in Traumatic Brain Injury

间充质干细胞分泌组的调节治疗创伤性脑损伤中的小胶质细胞损伤

• 批准号: 10626686
• 负责人: Rajashekhar Gangaraju
• 金额: $ 53.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626686
• 关键词: Address; Adipose tissue; Agonist; Alzheimer' s Disease; Anti-Inflammatory Agents; Attention; Attenuated; Biological; Biological Response Modifier Therapy; Blindness; Brain; CD44 gene; Cause of Death; Cell Therapy; Chemistry; Clinical; Cognitive; Communicable Diseases; Data; Disease; Disease associated microglia; Dose; Economic Burden; Environment; Event; Generations; Genetic Transcription; Goals; Health Sciences; Hematology; Histologic; Impaired cognition; Inflammation; Injury; Knowledge; Label; Laboratories; Lipopolysaccharides; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Methods; Microglia; Modeling; Molecular; Molecular Analysis; Mus; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Organ; Pathology; Phagocytosis; Pharmacology; Phenotype; Pre-Clinical Model; Prevalence; Process; Proteins; Public Health; Publishing; Regulation; Research; Retina; Role; Route; Safety; Serum; Signal Pathway; Signal Transduction; Stromal Cells; TBI treatment; TSG-6 protein; TYROBP gene; Tennessee; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Traumatic Brain Injury; Universities; Vision; Visual; Visual impairment; World Health Organization; cognitive function; controlled cortical impact; disability; engineered exosomes; exosome; experience; functional outcomes; genetic approach; improved; improved functioning; in vivo; individualized medicine; inhibitor; innovation; knock-down; neurovascular; overexpression; preservation; public health relevance; receptor; regenerative; regenerative therapy; response; stem; stem cell biology; stem cell therapy; stem cells

ABSTRACT The World Health Organization predicts that traumatic brain injury (TBI) will surpass many diseases, including infectious diseases, as a significant cause of death and disabilities, including significant cognitive dysfunction and visual impairment. Mesenchymal stem/stromal cell (MSC) therapies have gained considerable attention as a strategy for protecting against neurodegenerative diseases. However, a poor understanding of the mechanisms of therapeutic action has hampered their regulatory approval for clinical use. We have pioneered the therapeutic application of adipose MSC-derived concentrated conditioned media (ASC-CCM), a "secretome" containing soluble proteins and exosomes, for neurovascular pathologies across a range of preclinical models. Guided by promising in vivo efficacy data and identification of TNF-Stimulated Gene-6 protein (TSG-6) as an exosome-cargo protein that suppresses microglial activation, we now propose studies to determine if non- invasive delivery of ASC-CCM protects against TBI-induced damage. We will test the central hypothesis that TSG-6 enriched ASC-CCM ameliorates the generation of TBI-induced disease-associated microglia (DAM), thereby modulating phagocytosis and inflammation to restore the microglial homeostatic state to protect visual and cognitive function. In Aim 1, using a validated controlled cortical impact model of TBI (CCI-TBI) with and without intranasal ASC-CCM treatment, we will a) establish the DAM phenotypic correlates of TBI-induced loss of cognitive and visual functions and b) establish the efficacy of ASC-CCM treatment in TBI. In Aim 2, using microglia in culture, we will determine if activation of the DAM signature through TYROBP-APOE4-axis signaling leads to phagocytosis and inflammation and determine how exosomal TSG-6 modulates TYROBP-APOE4- mediated DAM activation. In Aim 3, we will investigate the hypothesis that exosomes carrying TSG-6 protein are sufficient to modulate the activation of DAM signature and thus impart the therapeutic benefit in TBI. We will also study the distribution of exosomes in the tissues and study potential safety and toxicity. The proposed research is significant and innovative because our expected results would provide the rationale for developing mechanistically defined regenerative therapies tailored to modulating microglial phenotypes and signaling pathways involved in neurodegeneration. The PI's laboratories have been engaged for nearly a decade in developing regenerative and pharmacological therapies for neurotrauma and are well suited to conduct studies proposed in this application. Our environment at the University of Tennessee Health Science Center and Diadem Biotherapeutics, Inc makes us uniquely qualified to pursue this objective, given the extensive collective experience in molecular and stem cell biology, exosome engineering, proinflammatory signaling networks, and neurotrauma models.

摘要 世界卫生组织预测，创伤性脑损伤（TBI）将超过许多疾病，包括 传染病是死亡和残疾的重要原因，包括严重的认知功能障碍 和视力障碍。间充质干细胞/基质细胞（MSC）疗法已经获得相当大的关注， 一种预防神经退行性疾病的策略。然而，对 治疗作用机制阻碍了它们的临床应用的监管批准。我们开创 脂肪MSC衍生的浓缩条件培养基（ASC-CCM）的治疗应用， 包含可溶性蛋白质和外来体，用于一系列临床前模型中的神经血管病理学。 在有希望的体内疗效数据和TNF刺激的基因-6蛋白（TSG-6）作为肿瘤抑制剂的鉴定的指导下， 外泌体货物蛋白抑制小胶质细胞激活，我们现在提出的研究，以确定是否非- ASC-CCM的侵入性递送保护免受TBI诱导的损伤。我们将检验中心假设， 富含TSG-6的ASC-CCM改善TBI诱导的疾病相关小胶质细胞（DAM）的产生， 从而调节吞噬作用和炎症，以恢复小胶质细胞的稳态， 和认知功能。在目标1中，使用经验证的TBI控制皮质撞击模型（CCI-TBI）， 在没有鼻内ASC-CCM治疗的情况下，我们将a）建立TBI诱导的损失的DAM表型相关性， 和B）确立ASC-CCM治疗TBI的功效。在目标2中，使用 在培养的小胶质细胞中，我们将确定是否通过TYROBP-APOE 4轴信号转导激活DAM信号 导致吞噬作用和炎症，并确定外泌体TSG-6如何调节TYROBP-APOE 4- 介导的DAM激活。在目的3中，我们将研究携带TSG-6蛋白的外泌体是 足以调节DAM信号的激活，从而赋予TBI的治疗益处。我们将 还研究外泌体在组织中的分布，并研究潜在的安全性和毒性。拟议 研究是重要的和创新的，因为我们的预期结果将为开发 调节小胶质细胞表型和信号传导的机制定义的再生疗法 参与神经退化的途径。PI的实验室已经从事了近十年， 开发神经创伤的再生和药理学疗法，非常适合进行研究 本申请中提出的。我们在田纳西大学健康科学中心和Diadem的环境 Biotherapeutics，Inc使我们唯一有资格追求这一目标，鉴于广泛的集体 在分子和干细胞生物学，外泌体工程，促炎信号网络， 神经创伤模型