Pathological Mechanisms of Immune-Mediated Cerebellar Ataxia with Associated Sez6L2 Autoantibodies

免疫介导的小脑共济失调与相关 Sez6L2 自身抗体的病理机制

• 批准号: 10740682
• 负责人: JENNETTA W HAMMOND
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10740682
• 关键词: Abnormal coordination; Administrative Supplement; Animals; Antibodies; Ataxia; Autoantibodies; Autoimmune; Autoimmunity; B-Lymphocytes; Behavior assessment; Biological Markers; Bradykinesia; Brain; Brain region; Case Study; Cells; Cerebellar Ataxia; Cerebellum; Cognitive deficits; Complement; Coupled; Cytotoxic T-Lymphocytes; Disease; Flow Cytometry; Gait Ataxia; Health; Human; Immune; Immune response; Immune system; Immunization; Immunize; Immunohistochemistry; Immunosuppression; Immunotherapy; In Vitro; Integral Membrane Protein; Limb Ataxia; Link; Mediating; Mentors; Minority Graduate Student; Mouse Strains; Movement; Mus; Neurons; Parkinsonian Disorders; Pathologic; Pathology; Patients; Phenotype; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Proteins; Purkinje Cells; Reporting; Research Project Grants; Research Support; Risk; Speech; Symptoms; Testing; Underrepresented Minority; Viral Vector; autoimmune pathogenesis; career development; falls; granule cell; immune cell infiltrate; motor symptom; mouse model; neuroimmunology; novel therapeutics; oculomotor; parent grant; research and development; routine screening; vaccination strategy

Project Summary/Abstract Parent Grant Project: Sez6L2 autoantibodies have been reported in patients with subacute cerebellar ataxia. Patients present with gait ataxia, slurred speech, and ocular motor symptoms. Some patients also develop limb ataxia, cognitive deficits, bradykinesia, and/or Parkinsonism. These case studies have led to the hypothesis that autoimmunity against Sez6L2 can directly cause cerebellar damage leading to ataxia. Sez6L2 is a transmembrane protein expressed by most neurons in the brain including Purkinje cells and granule cells of the cerebellum. Currently, no animal studies have been performed to help understand if Sez6L2 autoantibodies are directly pathologic, whether they are a biomarker of cell-based autoimmunity to Sez6L2, or whether are simply superfluous to the cerebellar pathology. We plan to test two mouse models of Sez6L2 autoimmunity in order to understand the mechanisms underlying cerebellar ataxia with associated Sez6L2 autoantibodies. Aim 1 of this project will determine whether mice immunized with Sez6L2 protein develop cerebellar ataxia. We will also seek to understand the disease mechanisms using behavioral assessments, immunohistochemistry, and flow cytometry analysis of infiltrating immune cell populations. Aim 2 will determine whether Sez6L2 antibodies alone can cause cerebellar ataxia in mice, or block Sez6L2's complement inhibitory functions in vitro. We anticipate that these studies will provide strong mechanistic evidence that the antibody and/or full immune response to Sez6L2 is a pathological cause of ataxia and related symptoms. These studies, coupled with the presently reported human case studies, should encourage prompt and routine screening for Sez6L2 autoantibodies in suspected immune-mediated presentations of cerebellar ataxia. The results on disease mechanisms could also help guide clinicians to the immunotherapies that may be most effective for patients and help justify the risks of prolonged immunosuppression. Administrative Supplement to Support Diversity in Health-Related Research Project: This supplement will support the research and career development of an under-represented minority graduate student. The candidate's research project will expand Aim 1 to test different mouse strains for autoimmune susceptibility to Sez6L2 immunization and a new viral-vector based heterologous prime-boost immunization strategy. It will also test whether the ataxia phenotype in Sez6L2 immunized mice requires functional cytotoxic T cells or B cells. The mentored research and career development activities of this application will help prepare the candidate for graduation and obtaining a competitive postdoctoral position for continued study in the interdisciplinary field of neuroimmunology.

项目总结/文摘