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Toward Altered Probiotic Therapy for Phenylketonuria

改变苯丙酮尿症的益生菌疗法

基本信息

批准号：
9227238
负责人：
Nikhil Unni Nair
金额：
$ 7.19万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-18 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9227238
关键词：
Acute Adherence Adhesions Adult Adverse effects Affect Amino Acid Transporter Apical Area Bacteria Binding Binding Proteins Blood Cell surface Child Chronic Classical phenylketonuria Complex Development Diet Disease Drug Kinetics Engineering Ensure Enzymes Equilibrium Essential Amino Acids Family Fetus Foundations Funding Future Genetic Goals Hereditary Disease Hybrids Hyperphenylalaninaemias In Vitro Inborn Genetic Diseases Infant Intervention Intestines Lactobacillus reuteri Letters Metabolic Diseases Metabolism Microbe Molecular Conformation Mothers Mucous body substance Names Neurologic Oral Organism Pathology Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phenylalanine Phenylalanine Ammonia-Lyase Phenylketonurias Polyethylene Glycols Pregnant Women Probiotics Protein Hybridization Proteins Quality of life Resources Risk Signal Transduction Small Intestines Spontaneous abortion Surface Symbiosis System Techniques Tertiary Protein Structure Therapeutic Time Toxic effect Variant Work absorption base density design developmental disease effective therapy enzyme replacement therapy extracellular flexibility holistic approach hybrid protein microbial monomer mouse model novel strategies novel therapeutics overexpression polypeptide pregnant probiotic therapy residence small molecule success technology development tetrahydrobiopterin

项目摘要

Summary The severe acute and chronic developmental and neurological impacts of PKU seen in infants and adults are due to the presence of high concentrations of phenylalanine (Phe) in the blood. In pregnant mothers with PKU, high Phe levels significantly increase the risk of miscarriage or severe developmental disorders in the growing fetus. The adverse effects of PKU can be alleviated by lowering systemic levels of Phe, and various interventions (pharmacological, enzymatic, and diet-related) have been attempted with some success. This work is based on that hypothesis that highly active enzymes delivered by probiotic bacteria that utilize Phe as substrate can re- direct its flux away from the apical amino acid transporters in the gut and thus minimize Phe absorption in the gut. The long-term goal of this work is to develop this Altered Probiotic Therapy (APT) approach for the treatment of PKU. The objective of this proposal is to engineer the activity of a probiotic organism to deliver therapeutic Phenylalanine Ammonia Lyase (PAL) enzyme to the gut and to enhance residence time for efficient Phe depletion. The APT approach can provide a novel and holistic approach to treating the various Phe-related metabolic disorders including PKU, maternal PKU, and hyperphenylalaninemia (HPA).

概括 PKU 对婴儿和成人的严重急性和慢性发育和神经系统影响是由于血液中存在高浓度的苯丙氨酸（Phe）。在患有 PKU 的孕妇中，高 Phe 水平会显着增加流产或生长中严重发育障碍的风险胎儿。 PKU 的不良反应可以通过降低 Phe 的全身水平和各种干预措施来减轻（药理学、酶学和饮食相关的）已经尝试并取得了一些成功。这项工作是基于该假设认为，利用苯丙氨酸作为底物的益生菌传递的高活性酶可以重新引导其通量远离肠道中的顶端氨基酸转运蛋白，从而最大限度地减少 Phe 在肠道中的吸收肠道。这项工作的长期目标是开发这种改变益生菌疗法（APT）的方法 PKU 的治疗。该提案的目的是设计益生菌的活性以提供治疗性苯丙氨酸氨裂解酶 (PAL) 进入肠道并延长停留时间，以提高效率苯丙氨酸耗尽。 APT 方法可以提供一种新颖且整体的方法来治疗各种 Phe 相关疾病代谢性疾病，包括 PKU、母体 PKU 和高苯丙氨酸血症 (HPA)。