TRAUMATIC BRAIN INJURY AND CELLULAR HOMEOSTASIS

钙（Ca2+）稳态的维持不仅对正常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，例如在创伤性脑损伤（TBI）后发生的，Ca2+的线粒体循环是这种Ca2+稳态和因此细胞稳态的关键。线粒体对Ca2+的过度螯合使电子传递与ATP合成解偶联，导致自由基产生增加，并打开线粒体渗透性转换孔（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（Δ Psi），导致胞质溶胶中过量的Ca2+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，在受伤后需求量很大。 如果没有足够的ATP来源，细胞就难以维持Ca2+稳态。 该提议的中心假设是线粒体的Ca 2+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，其抑制MPTP的开放并维持线粒体的稳态。我们有强有力的证据表明，全身注射CsA显着减少TBI动物模型中的神经元死亡。本提案的具体目的是检验以下假设：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）抑制TBI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TBI后突触可塑性。 这些研究将显著提高我们对TBI后机制的理解，并有望导致治疗，从而增加恢复。

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.