Traumatic brain injury (TBI) is a leading cause of mortality and disability in younger adults worldwide, with an estimated US incidence of 1.5 million per year in the general population. The annual economic costs in the US were estimated at US$76.5 billion. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all TBIs, and a significant portion of mTBI patients suffer from long lasting o even permanent post-concussive syndromes. Repetitive mTBI from multiple concussions is of particular concern for individuals engaged in contact sports or in military operations. Currently no pharmacological therapy is available that augments functional recovery or prevents long-term neuropsychological symptoms associated with TBI. Transforming growth factor-? (TGF-?) is an important injury response factor in the brain and has been implicated in various neurological diseases and in TBI. Using our recently developed mouse model of repetitive mTBI, our preliminary data show that TGF-? is dysregulated after repetitive mTBI and that SRI-011381, a novel small molecule TGF-? agonist developed at Stanford University, when applied 24 h after injury, reduces cognitive deficits and neuroinflammation. Based on these findings, we propose to investigate the long-term changes and the role of TGF-? signaling in repetitive mTBI and to investigate whether activating TGF-? signaling through SRI- 011381 can reduce long-term cognitive deficits and neuropathology associated with repetitive mTBI. In addition to the wide therapeutic time window of SRI-011381, our proposal builds and expands on the results from the extensive preclinical efficacy, pharmacology and toxicology studies in which our lab has been involved. Our ultimate goal is to develop SRI-011381 for clinical testing as a therapeutic for patients with repetitive mTBI. We hope that our clinically relevant experimental design, along with the advantages of SRI-011381 will increase the likelihood of success in clinical testing.
Repeated mild traumatic brain injury (concussion) can cause sustained damage to the brain in humans, and currently there is no effective treatment to promote recovery. This proposal will investigate a novel therapeutic strategy in preclinical studies. Results obtained from the proposed research would facilitate clinical testing of this strategy and eventually benefit patients with concussive injury.
| Tesseur, Ina; Nguyen, Andy; Chang, Betty et al. (2017) Deficiency in Neuronal TGF-? Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-? Signaling Protects against MPTP Neurotoxicity in Mice. J Neurosci 37:4584-4592 |
| Zhang, Xiao-Dong; Wang, Huasen; Antaris, Alexander L et al. (2016) Traumatic Brain Injury Imaging in the Second Near-Infrared Window with a Molecular Fluorophore. Adv Mater 28:6872-9 |
