Unlocking microglia targeting for neurotherapeutics

解锁神经治疗药物的小胶质细胞靶向

• 批准号: 10696509
• 负责人: Mariko L. Bennett
• 金额: $ 44.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696509
• 关键词: Acceleration; Affect; Anti-Retroviral Agents; Award; Benchmarking; Bone Marrow; Brain; CRISPR screen; Cell Therapy; Cells; Central Nervous System; Child Care; Childhood; Chimera organism; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Custom; Engineered Gene; Engineering; Ensure; Future; Gene Expression; Genes; Genetic; Genetic Engineering; Genome; Goals; Growth; HIV; Herpes encephalitis; Immune; Impaired cognition; In Vitro; Infection; Injury; Institution; Interferons; Knock-out; Knockout Mice; Lentivirus; Libraries; Light; Link; Macrophage; Mediating; Mediator; Mentors; Mentorship; Methods; Microglia; Molecular; Mus; Neuroglia; Neuroimmune; Neurologic; Neurologist; Neurology; Neurons; Nucleic Acids; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Philadelphia; Point Mutation; Postdoctoral Fellow; Predisposition; Production; Recombinant adeno-associated virus (rAAV); Regulation; Research; Resistance; Resources; Role; Signal Transduction; Spinal Cord; Stimulator of Interferon Genes; Students; Surveys; Testing; Tissues; Training; Transgenic Mice; Transplantation; Tropism; Validation; Vesicular stomatitis Indiana virus; Viral; Viral Physiology; Virus Diseases; Vision; Work; antiviral immunity; brain cell; design; frontier; gain of function; gene therapy; in vivo; inhibitor; insight; lentivirally transduced; leukodystrophy; multidisciplinary; nervous system disorder; neuroimmunologic disease; novel strategies; novel therapeutics; preservation; prevent; professor; programs; receptor; residence; response; sensor; single-cell RNA sequencing; targeted treatment; therapeutic target; therapy development; tool; transcriptome; transcriptomics; transduction efficiency

PROJECT SUMMARY/ABSTRACT Microglia are the long-lived resident macrophages of the brain and spinal cord, which constantly survey the microenvironment to respond rapidly to injury and infection. Unlike neurons or other glia, microglia are transplantable, making them ideal candidates for targeted therapies to treat neurological diseases. A major barrier to creating and refining such treatments is an inability to genetically engineer microglia with lentiviruses. This proposal aims to identify and overcome microglia restriction factors to enable gene editing with lentiviruses and gain insights into microglia-mediated antiviral immunity. Aim 1 will test the hypothesis that cGAS/STING, a known anti-viral pathway, underlies microglial viral restriction using inhibitors and transgenic mouse microglia in vitro, with in vivo validation using a new microglia-specific Cre mouse. In Aim 2, I will perform an unbiased microglia-focused CRISPR knockout screen using newly created AAVs with microglia tropism to discover new anti-viral pathways that prevent lentiviral infection. Aim 2 demonstrates the first CRISPR screen in primary microglia. This Early Independence application offers a vision for my independent research program. It is based on a platform of microglia-based discovery tools I created over the last decade, and driven by my work as a pediatric neurologist who cares for children with neuroimmunological conditions including leukodystrophies and interferonopathies. It will provide new approaches to genetic targeting of microglia for neurotherapeutics, direct testing of microglia antiviral immunity, and will influence future directions related to the neurological sequelae of HIV latency and the pathogenesis of neuroimmunological disease.

项目总结/文摘