Effect of cysteine on glutathione production in critically ill neonates

描述（由申请人提供）：候选人是加州大学洛杉矶分校大卫格芬医学院的儿科外科医生和外科助理教授，其长期目标是成为一名独立的临床医生-科学家，其研究将对减少新生儿所患疾病产生重大影响。通过指导经验丰富的科学研究人员作为导师和广泛的教育，研究和临床设施的网络，在加州大学洛杉矶分校，本提案的目的是促进候选人的学术生涯发展超过五年的时间。该提案涉及获得培训，成为一名独立的临床科学家，同时研究半胱氨酸对抗氧化剂谷胱甘肽的产生及其对危重新生儿氧化组织损伤的影响。低水平的半胱氨酸和谷胱甘肽已被证明在危重新生儿中，这些新生儿具有与氧化损伤相关的高发病率，如慢性肺病和坏死性小肠结肠炎。半胱氨酸是谷胱甘肽合成的限速底物，但它不易于由危重的胃肠外喂养的新生儿合成，也不能常规给予。候选人假设，与未补充半胱氨酸的类似新生儿相比，在常规肠外营养的同时补充半胱氨酸的危重新生儿将具有更高的谷胱甘肽合成率和储存水平，随后将导致细胞因子炎症反应减少，氧化组织损伤减少，氧化损伤相关疾病的严重程度降低。为了检验这一假设，提出了一项对喂食等氮肠外营养的危重新生儿补充半胱氨酸的随机、前瞻性、双盲临床试验，具体目的如下：（1）利用新的非放射性物质，测量红细胞谷胱甘肽的总浓度、红细胞谷胱甘肽的氧化还原比和红细胞谷胱甘肽的体内合成速率，用[13 C]-甘氨酸的稳定同位素示踪技术，（2）测量血浆白细胞介素-6、肿瘤坏死因子-α和丙二醛浓度作为炎症反应严重程度和氧化性组织损伤程度的决定因素，和（3）测量机械通气、补充氧气，和住院作为疾病严重程度的主要临床结局。所获得的数据应提供深入了解以前未表征的谷胱甘肽合成的体内动力学和危重新生儿氧化组织损伤的发病机制，以及建议潜在的治疗方法，以提高抗氧化防御，如半胱氨酸补充剂。这项研究的结果可能最终改变危重新生儿的标准营养和治疗实践，以改善这些极其脆弱的患者的结局。

DESCRIPTION (provided by applicant): The candidate is a pediatric surgeon and Assistant Professor of Surgery at the David Geffen School of Medicine at UCLA, whose long-term goal is to become an independent clinician-scientist with research that will make a significant impact on diminishing the illnesses endured by neonates. Through the guidance from experienced scientific investigators as mentors and an extensive network of educational, research, and clinical facilities available at UCLA, the purpose of this proposal is to foster the candidate's academic career development over a five-year period. The proposal involves acquiring the training to become an independent clinician-scientist while investigating the effect of cysteine on the production of the antioxidant glutathione and its impact on oxidative tissue injury in critically ill neonates. Low levels of cysteine and glutathione have been demonstrated in critically ill neonates who have a high incidence of disease associated with oxidative-injury, such as chronic lung disease and necrotizing enterocolitis. Cysteine is the rate limiting substrate for the synthesis of glutathione, but it is not readily synthesized by nor routinely given to critically ill, parenterally fed neonates. The candidate hypothesizes that critically ill neonates administered cysteine supplementation with their routine parenteral nutrition will have a higher rate of synthesis and stored levels of glutathione that will subsequently result in a diminished cytokine inflammatory response, less oxidative tissue injury, and a decrease in the severity of oxidative-injury associated diseases compared to similar neonates without cysteine supplementation. To test this hypothesis, a randomized, prospective, double-blinded, clinical trial of cysteine supplementation to critically ill neonates fed isonitrogenous parenteral nutrition is proposed with the following specific aims: (1) to measure total concentrations of erythrocyte glutathione, redox ratios of erythrocyte glutathione, and the in vivo synthetic rates of erythrocyte glutathione utilizing a novel non-radioactive, stable isotope tracer technique with [13C]-glycine, (2) to measure plasma interleukin-6, tumor necrosis factor-a, and malondialdehyde concentrations as determinants of inflammatory response severity and degree of oxidative tissue injury, and (3) to measure the duration of mechanical ventilation, supplemental oxygen, and hospitalization as primary clinical outcomes of disease severity. The data obtained should provide insight into the previously uncharacterized in vivo kinetics of glutathione synthesis and the pathogenesis of oxidative tissue injury in critically ill neonates, as well as suggesting potential therapeutic approaches to improve antioxidant defense, such as cysteine supplementation. The result of this investigation could ultimately change the standard nutritional and treatment practices for critically ill neonates in order to improve the outcome for these extremely fragile patients.