MYELIN BASIC PROTEIN-LIKE MATERIAL--DELAYED MYELOGENESIS MONITOR

这项建议基于这样的假设，即尿肽的水平 与髓鞘碱性蛋白（MBP）呈免疫反应性， 髓鞘生成，并可以提供监测成功或失败的 儿童的髓鞘形成 不确定的过程，亚临床 参与和临床和生物学异质性， MR/DD患者人群尝试治疗或 基于临床评价的干预性试验困难，时间长 持续时间，而且往往是不确定的。 在某种程度上，这个问题代表了 无法充分评估损伤或神经发育失败， 准确地 这一提议是一种潜在的强有力的手段， 以非侵入性的方式解决这个问题， 诊断和预后能力以及监测有效性 干预策略。 本研究的具体目的是：（A）记录规范性 根据MBPLM的存在，髓鞘形成的发育过程 从出生到4岁的尿液中（研究1）;（B）确定 在极低出生体重（VLBW），小于1000克，高风险抽样中 对于脑室周围白质软化症（PVL）和异常髓鞘生成， 出生时至4岁时存在MBPLM（研究2）;（C）至 对极低出生体重儿童从出生到4岁进行纵向研究， 年龄，以确定个体生长曲线并测试性别 MBPLM随时间的差异（研究3）;（D）与MBPLM水平相关 及其随时间的变化与MR/DD临床表现的关系 VLBW儿童的横截面和纵向样本;（E）至 通过高效液相色谱法（HPLC）表征 出生时至4岁MBPLM的特征;（F）寻找 存在由外显子2或MBP编码的MBPLM，仅在 （G）寻找存在的物质交叉反应， 与MBP的瓜氨酸化（C8）异构体，在第一个充电 异构体在髓鞘形成过程中出现;和（H）获得存档 关于儿童MBPLM水平的临床数据库（研究4）， 相对罕见的发育障碍与疾病 髓鞘生成，例如甲状腺功能减退、脑白质营养不良、有机酸 疾病和氨基酸疾病（包括PKU）。 我们认识到，拟议的研究是探索性的， 产生有意义的信息。 然而，可靠的非侵入性标记物 髓鞘形成的能力。 这种最近的方法论 这一突破提供了一个独特的机会， 神经发育特征，在良好的建立和划定 有髓鞘生成标志物的队列。 因此，这些研究 提高了解正常人的知识的巨大潜力 和异常的发展。

This proposal rests on the hypothesis that the level of a urinary peptide which is immunoreactive with myelin basic protein (MBP) correlates with myelinogenesis and can provide a monitor of successful or failed myelinogenesis in children. The uncertain course, subclinical involvement and clinical and biological heterogeneity within the population of MR/DD patients render attempts at therapeutic or interventional trials based on clinical evaluation difficult, of long duration, and often inconclusive. To some extent, the problem represents an inability to assess injury or failed neurodevelopment adequately and accurately. This proposal represents a potentially powerful means of addressing this issue in a noninvasive manner and the advancing diagnostic and prognostic capabilities and monitoring the effectiveness of intervention strategies. The specific aims of this study are: (A) to document the normative developmental course of myelinogenesis in terms of the presence of MBPLM in urine from birth through 4 years of age (Study 1); (B) to determine in a very low birthweight (VLBW), less than 1000 gm, sample at high risk for peri-ventricular leukomalacia (PVL) and abnormal myelinogenesis, the presence of MBPLM at birth through 4 years of age (Study 2); (C) to conduct a longitudinal study of VLBW children from birth to 4 years of age to ascertain individual growth curves and to test for gender differences in MBPLM over time (Study 3); (D) to relate levels of MBPLM and their changes over time to clinical manifestations of MR/DD in the cross-sectional and longitudinal samples of VLBW children; (E) to characterize by high performance liquid chromatography (HPLC) the features of MBPLM at birth through 4 years; (F) to search for the presence of MBPLM encoded by exon 2 or MBP, expressed only during myelinogenesis; (G) to search for the presence of material cross-reactive with the citrullinated (C8) isomer of MBP, among the first charged isomers to appear during myelinogenesis; and (H) to acquire an archival clinical database on MBPLM levels in children (Study 4) with specific, relatively rare developmental disabilities associated with disorders of myelinogenesis, e.g. hypothyroidism, leukodystrophies, organic acid disorders, and amino acid disorders (including PKU). We recognize that the proposed studies are exploratory in terms of yielding meaningful information. However, reliable non-invasive markers of myelinogenesis re presently lacking. This recent methodologic breakthrough provides a unique opportunity to correlate neurodevelopmental characteristics in well-established and delineated cohorts with a marker of myelinogenesis. Thus, these studies have substantial potential for advancing knowledge about understanding normal and aberrant development.