Project Grant R01NS132772

ACSDKP AS A NOVEL TREATMENT FOR TRAUMATIC BRAIN INJURY - PROJECT SUMMARY/ABSTRACT TRAUMATIC BRAIN INJURY (TBI) IS A LEADING CAUSE OF LONG-TERM DISABILITY IN THE UNITED STATES AND A POTENTIAL RISK FACTOR FOR DEVELOPING ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE RELATED DEMENTIAS (AD/ADRD). TO DATE, NO EFFECTIVE THERAPEUTIC AGENTS HAVE BEEN IDENTIFIED FROM TBI CLINICAL TRIALS. THERE IS A COMPELLING NEED TO DEVELOP NOVEL THERAPEUTIC TREATMENTS FOR TBI. THE OBJECTIVE OF THIS PROJECT IS TO TEST AND DEVELOP A TETRAPEPTIDE N-ACETYL- SERYL-ASPARTYL-LYSYL-PROLINE (ACSDKP) AS A NOVEL TREATMENT FOR TBI, AND TO INVESTIGATE MECHANISMS UNDERLYING ACSDKP TREATMENT-ENHANCED FUNCTIONAL RECOVERY AFTER TBI. OUR DATA DEMONSTRATE THAT 3-DAY SUBCUTANEOUS INFUSION OF ACSDKP INITIATED 1H AFTER TBI SIGNIFICANTLY IMPROVES FUNCTIONAL OUTCOME IN A RAT CONTUSION MODEL OF TBI INDUCED BY CONTROLLED CORTICAL IMPACT (CCI) INJURY. OUR DATA FURTHER SHOW THAT ACSDKP NOT ONLY PROVIDES NEUROPROTECTION BY REDUCING FIBRIN ACCUMULATION, LESION VOLUME AND HIPPOCAMPAL NEURONAL LOSS BUT ALSO PROMOTES NEUROVASCULAR REMODELING INCLUDING ANGIOGENESIS, SYNAPTOGENESIS, AND NEUROGENESIS. THESE FINDINGS INDICATE THAT ACSDKP HAS PROMISE AS AN EFFECTIVE TREATMENT FOR TBI. OUR PRELIMINARY DATA DEMONSTRATE THAT ACSDKP TREATMENT SIGNIFICANTLY DECREASES TRANSFORMING GROWTH FACTOR BETA 1 (TGF-B1) AND NUCLEAR FACTOR-KAPPA B (NFKB) IN THE BRAIN OF TBI RATS. OF SIGNIFICANCE, ACSDKP SELECTIVELY REDUCES THE HISTONE DEACETYLASE 4 (HDAC4) NUCLEAR TRANSLOCATION AND INCREASES HISTONE H3 ACETYLATION, SUGGESTING THAT HDAC4 NUCLEAR TRANSLOCATION CONTRIBUTES TO TBI PATHOPHYSIOLOGY. BASED ON LITERATURE AND OUR ROBUST DATA, WE WILL TEST THE CENTRAL HYPOTHESIS THAT ACSDKP TREATMENT IMPROVES FUNCTIONAL RECOVERY AFTER TBI BY REDUCING NEUROINFLAMMATION, ENHANCING NEUROPROTECTION AND NEUROVASCULAR REMODELING BY INHIBITING TGF-B1/NFKB SIGNALING, AND REDUCING NUCLEAR TRANSLOCATION OF HDAC4. TO TEST THE CENTRAL HYPOTHESIS AND TO ACCOMPLISH THE OBJECTIVES OF THIS APPLICATION, WE PROPOSE THREE SPECIFIC AIMS. AIM 1 WILL DETERMINE THE DOSE-RESPONSE AND THE EFFECTIVE THERAPEUTIC WINDOWS OF ACSDKP FOR IMPROVEMENT OF FUNCTIONAL RECOVERY IN MALE AND FEMALE RATS AFTER TBI. AIM 2 WILL DETERMINE EFFECTS OF ACSDKP AT OPTIMAL DOSE AND THERAPEUTIC WINDOW ON ANGIOGENESIS, NEUROGENESIS, AXONAL REMODELING AND NEUROINFLAMMATION IN MALE AND FEMALE RATS AFTER TBI. AIM 3 WILL DETERMINE WHETHER TGF- B1/NFKB AND HDAC4 NUCLEAR TRANSLOCATION SIGNALING PATHWAYS CONTRIBUTE TO TBI PATHOPHYSIOLOGY AND ACSDKP- INDUCED THERAPEUTIC BENEFITS IN MALE AND FEMALE RATS AFTER TBI. COMPLETION OF THIS PROJECT WILL AID OUR UNDERSTANDING OF THE MECHANISMS UNDERLYING ACSDKP-PROMOTION OF FUNCTIONAL RECOVERY AFTER TBI. THIS PROPOSAL IS HIGHLY CLINICALLY RELEVANT, AND IF SUCCESSFUL WILL PROVIDE ESSENTIAL INFORMATION FOR FACILITATING DEVELOPMENT OF ACSDKP AS A NOVEL THERAPY FOR TBI AND HAVE A SIGNIFICANT IMPACT ON QUALITY OF LIFE FOR TBI PATIENTS.