Astroglial Monocarboxylate Transporter (MCT) Pathway in Neurodegeneration

描述（由申请人提供）：越来越多的证据表明，星形胶质细胞对于支持正常神经元功能至关重要，星形胶质细胞功能障碍可能导致许多神经退行性疾病。星形胶质细胞的一个重要功能是将营养物质从毛细血管运输到神经元。大部分营养支持是以葡萄糖的形式;然而，理论上，涉及乳酸的替代途径也可能是神经元能量的重要来源。星形胶质细胞通过糖酵解产生大量的乳酸，乳酸可以通过不同的分子亚种-星形胶质细胞中的MCT 1、MCT 4和神经元上的MCT 2从星形胶质细胞转运到神经元。最近在体内的研究表明，兴奋性传输可能是调节-部分-通过网络星形胶质细胞调节神经元代谢。在体外，外源性乳酸或与星形胶质细胞共培养能够防止由葡萄糖剥夺诱导的神经元细胞死亡。星形胶质细胞的这种保护功能在用星形胶质细胞乳酸转运蛋白MCT 1和MCT 4的抑制剂处理时丧失。 在这个建议中，我们将首先确定是否星形胶质细胞的乳酸输出的MCT 1或MCT 4是必要的神经元存活在体外。这些研究将检验星形胶质细胞乳酸输出是神经元的基本星形胶质细胞支持途径的假设。然后，我们将确定星形胶质细胞乳酸转运蛋白MCT 1/MCT 4是否是A）体内正常神经元功能/活性的参与者和B）体内神经元存活所必需的。我们假设星形胶质细胞MCT转运蛋白可能是正常神经元功能所必需的。最后，我们将确定MCT表达的失调是否有助于ALS模型中的神经变性，以及该途径的修复是否具有神经保护作用。 总体而言，我们假设星形胶质细胞通过星形胶质细胞特异性转运蛋白MCT 1/MCT 4通过必需的乳酸转运/输出来支持神经元，并且该途径是神经变性中星形胶质细胞功能障碍的重要部分，并导致ALS等疾病中的运动神经元死亡。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that astrocytes are critical for the support of normal neuronal function, and astrocyte dysfunction may contribute to a number of neurodegenerative diseases. One important function of astrocytes is to transport nutrients from capillaries to neurons. Much of the nutritional support is in the form of glucose; however, it has been theorized that an alternate pathway, involving lactate, may also be an important source of energy for neurons. Astrocytes produce high amounts of lactate through glycolysis, and lactate can be transported from astrocytes to neurons via distinct molecular subspecies- MCT1, MCT4 in astroglia and MCT2 on neurons. Recent in vivo studies suggest that excitatory transmission may be regulated- in part - by networked astrocyte regulation of neuronal metabolism. In vitro, exogenous lactate or co-culturing with astrocytes is able to prevent the neuronal cell death induced by glucose deprivation. This protective function of astrocytes is lost by treatment with inhibitors to astroglial lactate transporters MCT1 and MCT4. In this Proposal we will first determine if astroglial lactate export by MCT1 or MCT4 is necessary for neuronal survival in vitro. These studies will test the hypothesis that astroglial lactate export is a fundamental astroglial support pathway for neurons. We will then determine if astroglial lactate transporters MCT1/MCT4 are A) Participants in normal neuronal function/activity in vivo and B) are necessary for neuronal survival in vivo. We hypothesize that Astroglial MCT transporters are likely to be necessary for normal neuronal function. Finally we will determine if dysregulation of MCT expression contributes to the neurodegeneration in ALS models if and repair of this pathway is neuroprotective. Overall, we hypothesize that astrocytes support neurons via essential lactate transport/export thru astrocyte specific transporters MCT1/MCT4 and that this pathway is a significant part of astroglial dysfunction in neurodegeneration and contributes to motor neuron death in diseases like ALS.