TRAUMATIC BRAIN INJURY AND CELLULAR HOMEOSTASIS

维持钙稳态不仅对细胞的正常功能非常重要，而且对细胞的生存也非常重要。在兴奋性毒性损伤中，如创伤性脑损伤(TBI)后发生的钙离子的线粒体循环，是这种钙稳态的关键，因此细胞稳态。线粒体对钙的过度隔离使ATP合成中的电子传递解偶联，导致自由基的产生增加，线粒体通透性转换孔(MPTP)打开。MPTP是细胞死亡级联反应的重要组成部分。MPTP的开放取消了线粒体跨膜电位(Delapsi)，导致胞浆中过量的钙和自由基。三角肌的维持对于ATP的合成至关重要，ATP是细胞的主要能量来源，损伤后对ATP的需求很大。如果没有足够的三磷酸腺苷来源，细胞在维持钙稳态方面存在问题。这一建议的中心假设是，线粒体对钙的循环是兴奋性毒性神经元损伤的关键因素。环孢菌素A(CsA)是一种广泛使用的免疫抑制剂，它抑制MPTP的开放并维持线粒体的动态平衡。我们有强有力的证据表明，全身注射CsA显著减少了脑外伤动物模型中神经元的死亡。这一建议的具体目的是检验以下假设：1)稳定线粒体稳态将稳定脑损伤后的细胞稳态并保护皮质神经元，2)抑制脑损伤后MPTP的开放增强突触和线粒体的基本代谢功能，以及3)线粒体稳态促进脑损伤后突触的可塑性。这些研究将显著提高我们对脑外伤后机制的理解，并有望导致治疗方法的提高，从而提高康复。

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.