TRAUMATIC BRAIN INJURY AND CELLULAR HOMEOSTASIS

钙（Ca2+）稳态的维持不仅对正常的细胞功能，而且对细胞存活都是极其重要的。在兴奋性毒性损伤期间，如创伤性脑损伤（TBI）后发生的线粒体Ca2+循环是Ca2+内稳态和细胞内稳态的关键。线粒体对Ca2+的过度隔离使ATP合成中的电子传递不偶联，导致自由基的产生增加，并打开线粒体通透性过渡孔（MPTP）。MPTP是细胞死亡级联反应的重要组成部分。MPTP的开放消除了线粒体跨膜电位（deltapsi），导致细胞质中过量的Ca2+和自由基。德尔塔西的维持对ATP的合成至关重要，ATP是细胞的主要能量来源，在损伤后需求量很大。没有足够的ATP来源，细胞就有维持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 （Cyclosporin A, CsA）是一种广泛使用的免疫抑制剂，可抑制MPTP的开放，维持线粒体稳态。我们有强有力的证据表明，在TBI动物模型中，全身注射CsA可显著减少神经元死亡。本研究的具体目的是研究以下假设：1)稳定线粒体内稳态可以稳定脑损伤后细胞内稳态并保护皮层神经元；2)抑制脑损伤后MPTP的开放可以增强突触和线粒体的基本代谢功能；3)线粒体内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创伤性脑损伤后机制的理解，并有望导致提高恢复的治疗方法。

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.