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Targeting SNO-GAPDH in inflammatory neurodegeneration and mitochondrial injury

靶向 SNO-GAPDH 治疗炎症性神经变性和线粒体损伤

基本信息

批准号：
10398797
负责人：
Michael D Kornberg
金额：
$ 20.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398797
关键词：
Active Immunization Adaptive Immune System Address Area Attenuated Autopsy Biochemical Bioenergetics Biogenesis Biology Biotin Brain C57BL/6 Mouse Cell Death Cell Nucleus Central Nervous System Diseases Clinical Complement Data Demyelinating Diseases Demyelinations Development Plans Disease Experimental Autoimmune Encephalomyelitis Exposure to Flow Cytometry Foundations Free Radicals Future Genetic Goals Histopathology Human Immune Immune response Immune system Immunization Immunology Impairment Inflammation Inflammatory Injury Lymphoid Cell Measures Mediating Mentors Mentorship Methods Microglia Mitochondria Modeling Molecular Multiple Sclerosis Myelogenous Nerve Degeneration Neuraxis Neuroglia Neurologic Neurologic Deficit Neurons Neuroprotective Agents Nitric Oxide Nuclear Optic Nerve Oral Pathologic Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Phase Play Post-Translational Protein Processing Prevention Progressive Disease Proteins Relapse Research Respiration Retina Role SIRT1 gene SKIL gene Safety Signal Pathway Signal Transduction Spinal Cord System Techniques Therapeutic Therapeutic Human Experimentation Tissues Tumor-infiltrating immune cells Work adaptive immunity brain tissue career development cell type central nervous system injury chronic inflammatory disease clinical translation disability experimental study immune activation insight macrophage mitochondrial dysfunction mitochondrial metabolism mouse model multiple sclerosis patient neuroimmunology neuroinflammation neuroprotection novel novel therapeutic intervention novel therapeutics pre-clinical preclinical study prevent protective effect tool training opportunity white matter

项目摘要

PROJECT SUMMARY/ABSTRACT Although multiple sclerosis (MS) is classically considered a demyelinating disease, neuro-axonal loss occurs in both relapsing and progressive phases of the disease and represents the primary pathologic correlate of disa- bility. Existing therapies primarily target the peripheral immune system, preventing clinical relapses but largely failing to prevent neurodegeneration in progressive MS. Therapies with a primary neuroprotective mode of ac- tion are a major goal of current research, both to slow disability in progressive MS and to limit injury when re- lapses occur despite current therapies. Nitric oxide (NO), a toxic free radical produced by central nervous sys- tem (CNS) macrophages and microglia, contributes to neuro-axonal injury in both relapsing and progressive MS and in models of neuroinflammation, with NO-induced mitochondrial dysfunction playing a major role. Spe- cific, druggable signaling pathways that mediate this injury have not been identified. We propose to study a candidate signaling pathway involving nitrosylation of the protein GAPDH. Nitrosylated GAPDH (SNO-GAPDH) translocates to both nucleus and mitochondria, with an established role in cell death and nuclear targets, such as SIRT1 and PGC-1α, critical for mitochondrial bioenergetics. Moreover, SNO-GAPDH signaling can be blocked by CGP3466, a highly specific, oral CNS-penetrant drug with an established safety profile in humans and a low threshold for clinical translation. We have preliminary evidence that SNO-GAPDH signaling is active in an experimental autoimmune encephalomyelitis (EAE) mouse model of neuroinflammation, and in white matter tissue obtained post-mortem from MS patients. We have found that systemic administration of CGP3466 attenuates neurologic disability in C57BL/6 MOG35-55/CFA EAE and prevents impairment of neuronal mitochondrial respiration in cultured neurons exposed to NO. In the proposed studies, we plan to fully charac- terize SNO-GAPDH pathway activity in MOG35-55/CFA EAE and post-mortem human MS tissue. We will deter- mine whether the protective effects of CGP3466 in EAE derive from a primary neuroprotective mechanism in- dependent of peripheral immune effects, differentiating it from current therapies and establishing its pre-clinical potential. Finally, we will seek mechanistic insights by evaluating the effects of SNO-GAPDH on neuronal mito- chondrial function. Positive results from this mechanistic and pre-clinical therapeutic research will establish a new therapeutic approach for MS and neuroinflammatory disease more broadly. The PI's career development plan will provide new training opportunities in immunology, models of neuroinflammation, and mitochondrial bioenergetics, providing a foundation for future independent studies of inflammatory neurodegeneration.

项目总结/文摘