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