Identifying activators of interferon regulatory factors for neuroprotection

DESCRIPTION provided by applicant Stroke is a leading cause of morbidity and mortality in the United States However less than of patients are eligible for the current approved interventions of tissue plasminogen activator or thrombectomy We seek to develop new therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain an area of significant unmet medical need We have found that interferon regulatory factor IRF mediated gene transcription may represent an endogenous mechanism of neuroprotection that is associated with a reduction in ischemic injury Using both cell and mouse models of stroke we have demonstrated that administration of compounds following the ischemic insult that are known to induce IRF mediated gene transcription significantly reduces the extent of damage These results indicate that activation of IRF transcription factors following stroke may be a viable therapeutic intervention for the treatment of stroke patients The ultimate goal of this STTR program is to identify IRF activators with minimal off target immune activity and specificity for both mouse and human for preclinical development for stroke Our specific goal for this Phase I application is to develop and validate a high throughput screening platform to identify clinically viable IRF activating compounds for further development We propose the following aims Aim Validate a high throughput primary screening assay to identify potent and selective IRF activators using a human THP dual ISRE NF B reporter cell line and well format Aim Validate a high throughput secondary screening assay in mouse J cells containing dual ISRE NFkB reporters to evaluate cross species activity of primary hits from Aim Aim Verify the target and species selectivity of secondary hits by evaluating a panel of downstream IRF inducible genes in human and mouse brain derived cells PUBLIC HEALTH RELEVANCE Stroke is a leading cause of morbidity and mortality in the United States with approximately cases a year reported This proposal seeks to establish a high throughput screen for identification of compounds that activate interferon regulatory factors as potential mediators of neuroprotection with the ultimate goal being the development of a stroke therapeutic