TRAUMATIC BRAIN INJURY AND CELLULAR HOMEOSTASIS

维持钙 (Ca2+) 稳态不仅对于正常细胞功能而且对于细胞存活都极其重要。在兴奋性毒性损伤期间，例如创伤性脑损伤 (TBI) 后发生的情况，Ca2+ 的线粒体循环是 Ca2+ 稳态以及细胞稳态的关键。线粒体对 Ca2+ 的过度隔离使电子传输与 ATP 合成脱钩，导致自由基产生增加，并打开线粒体通透性转换孔 (MPTP)。 MPTP 是细胞死亡级联的重要组成部分。 MPTP 的打开消除了线粒体跨膜电位 (deltapsi)，导致细胞质中出现过量的 Ca2 和自由基。 维持 deltapsi 对于 ATP 的合成至关重要，ATP 是细胞的主要能量来源，损伤后对 ATP 的需求量很大。 如果没有足够的 ATP 来源，细胞就会出现维持 Ca2 稳态的问题。 该提议的中心假设是线粒体的 Ca2 循环是兴奋性毒性神经元损伤的关键因素。环孢素 A (CsA) 是一种广泛使用的免疫抑制剂，可抑制 MPTP 的开放并维持线粒体稳态。我们有强有力的证据表明，全身注射 CsA 可以显着减少 TBI 动物模型中的神经元死亡。该提案的具体目标是检验以下假设：1）稳定线粒体稳态将稳定细胞稳态并保护 TBI 后的皮质神经元，2）TBI 后抑制 MPTP 的开放可增强突触和线粒体的基本代谢功能，3）线粒体稳态可促进 TBI 后的突触可塑性。 这些研究将显着增强我们对 TBI 后机制的理解，并有望带来促进康复的治疗方法。

Maintenance of calcium (Ca2+) homeostasis is extremely important not only for normal cellular function but also cell survival. The mitochondrial cycling of Ca2+ during excitotoxic insults, such as that occurring after traumatic brain injury (TBI), is key to this Ca2+ homeostasis and hence cellular homeostasis. Excessive sequestering of Ca2+ by mitochondria uncouples electron transport from ATP synthesis leading to the increased production of free radicals, and opening of the mitochondrial permeability transition pore (MPTP). The MPTP is an important component contributing to the cell death cascade. Opening of the MPTP abolishes the mitochondrial transmembrane potential (deltapsi) resulting in excessive amounts of Ca2+ and free radicals in the cytosol. Maintenance of the deltapsi is critical for synthesis of ATP, the primary energy source for the cell, which is in great demand following injury. Without an adequate source of ATP the cell has a problem maintaining Ca2+ homeostasis. The central hypothesis of this proposal is that the cycling of Ca2+ by the mitochondria is a key element in excitotoxic neuronal damage. Cyclosporin A (CsA), a widely used immunosuppressant, inhibits the opening of the MPTP and maintains mitochondrial homeostasis. We have strong evidence that systemic injections of CsA significantly reduces neuronal death in an animal model of TBI. The specific aims of this proposal examine the following hypotheses: 1) that stabilizing mitochondrial homeostasis will stabilize cellular homeostasis and protect cortical neurons following TBI, 2) that inhibiting opening of the MPTP after TBI enhances basic metabolic functions of synapses and mitochondria, and 3) that mitochondrial homeostasis promotes synaptic plasticity following TBI. These studies will significantly enhance our understanding of the mechanisms following TBI and hopefully lead to therapies resulting in increased recovery.