Investigation of Brain Nitrogen Metabolism in Partial Ornithine Trascarbamylase

该项目的目标是验证大脑生化，白色物质和神经心理学生物标志物， 与部分鸟氨酸转氨甲酰酶受试者中高氨血症对大脑的影响相关 缺乏症（OTCD）。我们将使用神经成像（1H MRS [磁共振波谱]，DTI [扩散 张量成像]和功能磁共振成像[功能磁共振成像]）和神经心理学测试， 实现这一目标。这项拟议的研究代表了一个横截面的延续和扩展， 该联盟进行的成像研究（RDCRN 5104），已确定脑谷氨酰胺升高 (gin)和肌醇（ml）的减少作为OTCD患者中的特异性生物标志物。我们将进一步研究 这些生物标志物在三种氮负荷条件下的关系：1）在氮负荷期间和之后， 高氨血症发作; 2）临床和代谢稳定; 3）输注氮后 清除剂（Ammonul）。我们的工作假设是，杜松子酒和ml是相互关联的， OTCD中高氨血症（HA）的病理生理学。我们认为急性脑杜松子酒浓度升高预示着 急性HA。我们进一步假设，这种生化变化之后是渗透压的变化， 白色物质通过以ml为单位的消耗和DTI的变化检测。最后，我们提出，慢性杜松子酒升高 将在部分OTCD受试者中观察到，生物标志物偏离的严重程度将与 临床严重度。通过研究GIN和ML的变化幅度的影响， 我们将加强假设，即它们是因变量，因此 可作为可靠的生物标志物用于跟踪临床进程，并可用于开发新的治疗方法。

The goal of this project is to validate brain biochemical, white matter and neuropsychological biomarkers that correlate with the effect of hyperammonemia on the brain in subjects with partial ornithine transcarbamylase deficiency (OTCD). We will use neuroimaging (1H MRS [magnetic resonance spectroscopy], DTI [diffusion tensor imaging], and fMRI [functional magnetic resonance imaging]) and neuropsychological testing to realize this goal. This proposed research represents a continuation and expansion of a cross sectional imaging study (RDCRN 5104) performed by this consortium that has identified elevations in brain glutamine (gin) and reductions of myoinositol (ml) as specific biomarkers in patients with OTCD. We will further study the relationship of these biomarkers under three conditions of nitrogen load: 1) during and following a hyperammonemic episode; 2) at clinical and metabolic stability; 3) following an infusion of a nitrogen scavenging agent (Ammonul). Our working hypothesis is that gin and ml are related to one another in the pathophysiology of hyperammonemia (HA) in OTCD. We propose that acute brain gin elevations herald acute HA. We further hypothesize that this biochemical alteration is followed by osmotic changes in the white matter detected by depletion in ml and changes of DTI. Lastly, we propose that chronic gin elevations will be seen in subjects with partial OTCD and that the severity of biomarker deviation will correlate with clinical severity. By studying the effects of the magnitude of change in gin and ml independently and in relationship to one another, we will strengthen the hypothesis that they are dependent variables and as such can be used as reliable biomarkers to follow clinical course, and be useful in development of novel therapies.