Nitric Oxide and Bone Homeostasis in Patients with Argininosuccinate Lyase Deficiency

精氨基琥珀酸裂解酶缺乏症患者的一氧化氮和骨稳态

基本信息

批准号：
9329788
负责人：
Brendan Lee
金额：
$ 40.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9329788
关键词：
Address Affect Alpha Cell Ammonia Ancillary Study Architecture Arginine Argininosuccinate lyase deficiency Biology Bone Diseases Cardiovascular Diseases Caveolins Cell Lineage Cell model Cells Citrulline Clinical Research Coculture Techniques Complex Coupling Data Defect Dietary Nitrite Disease Dual-Energy X-Ray Absorptiometry Enteral Enzymes Equilibrium Exhibits Fibroblasts Fostering Genetic Genetic Models Genotype Goals Heat-Shock Proteins 90 Hereditary Disease Homeostasis Human Human Genetics Hyperammonemia Hypertension In Vitro Individual Intellectual functioning disability Intervention Trial Isotopes Knock-out Modeling Mus Natural History Nitric Oxide Nitric Oxide Synthase Nitrite Reductase Nitrites Osteoblasts Osteocalcin Osteoclasts Osteoporosis Outcome Pathway interactions Patients Peripheral Pharmacology Phenotype Physiological Processes Placebo Control Process Production Protein Isoforms Randomized Rare Diseases Reaction Recycling Regulation Role Salivary Secondary to Signal Transduction Signaling Molecule Site Source Supplementation TNFSF11 gene Therapeutic Therapeutic Intervention Therapeutic Studies Transgenic Organisms United States National Institutes of Health Urea argininosuccinate lyase argininosuccinate synthase base bone bone mass bone metabolism bone turnover density design dietary nitrate enzyme substrate extracellular in vivo induced pluripotent stem cell insight neurocognitive test osteoblast differentiation osteoclastogenesis response tool translational study treatment effect urea cycle

项目摘要

Project Summary Nitric oxide (NO), a ubiquitous signaling molecule, is important for most physiological processes including bone homeostasis. However, extensive in vitro and in vivo studies that have assessed the role of NO in bone biology have often yielded contrasting results. This is at least in part due to the fact that pharmacologic inhibition of nitric oxide synthases (NOS) or genetic models of NOS deficiency are limited by the redundancies of the NOS isoforms and cannot address the cell- autonomous roles of NO. Argininosuccinate lyase (ASL), is a urea cycle enzyme is not only required for the de novo synthesis of arginine, the substrate for NOS, but also to maintain the structural integrity of a NO-synthesis complex containing NOS, argininosuccinate synthase (ASS1), the arginine transporter CAT-1, and HSP90. Loss of ASL leads to non-redundant and cell-autonomous loss of NOS-dependent NO production and thus ASL deficiency (ASLD) is a human genetic disorder of NO production. The overall goals of this proposal are to study the role of NO in bone turnover, density, and architecture in a human model of NO deficiency and to understand the mechanistic basis by which NO affects bone metabolism. By leveraging an ongoing trial in this rare genetic disorder, we will address these specific questions: 1) Do patients with ASLD have abnormalities in bone turnover and bone mass and does NOS-independent NO supplementation affect these endpoints? 2) Do patient- derived induced pluripotent stem cells (iPSC) show differentiation defects along the osteoblastic lineage and how does this impact osteoclastic differentiation? 3) Do osteoblasts derived from patient- iPSC exhibit dysregulation of NO production due to dominance of a caveolin-dependent negative regulatory NOS complex? These studies could have a significant impact on the basic understanding of bone biology and foster translational studies in utilizing NOS-independent NO supplementation as a therapeutic intervention in the more common disorders like osteoporosis.

项目摘要一氧化氮（NO），一种无处不在的信号分子，对大多数生理学很重要包括骨稳态在内的过程。但是，具有广泛的体外和体内研究评估了NO在骨生物学中的作用通常会产生对比结果。至少部分是由于药理学抑制一氧化氮合酶（NOS）或遗传模型 NOS缺乏症受到NOS同工型的冗余的限制，无法解决细胞否。 Argininosccinate裂解酶（ASL）是尿素周期酶，不仅需要对于精氨酸的从头合成，NOS的底物，但也要维持结构含有NOS，精氨酸合酶（ASS1），精氨酸的无合成复合物的完整性转运蛋白CAT-1和HSP90。 ASL的丢失导致非冗余和细胞自主的损失 NOS依赖性无生产，因此ASL缺乏症（ASLD）是NO的人类遗传疾病生产。该提案的总体目标是研究NO在骨骼更新，密度和在人类模型中没有缺陷的建筑，并了解其机械基础没有影响骨代谢。通过利用正在进行的这种罕见遗传疾病的试验，我们将解决以下特定问题：1）ASLD患者的骨转换异常和骨骼质量和非依赖性不补充会影响这些终点吗？ 2）做病人 - 派生的诱导多能干细胞（IPSC）显示沿成骨细胞的分化缺陷谱系以及这如何影响破骨碎裂分化？ 3）做源自患者的成骨细胞 - IPSC由于小窝依赖性阴性的优势而表现出无生产的失调监管NOS复合体？这些研究可能会对骨骼生物学的基本理解和寄养翻译研究在利用NOS独立的无补充作为治疗方面干预更常见的骨质疏松症。