Diversity Supplement: BCM Center for Precision Medicine Models

多样性补充：BCM 精准医学模型中心

基本信息

批准号：
10877479
负责人：
Lindsay C Burrage
金额：
$ 7.54万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10877479
关键词：
Age Months Anabolism Anus Area Birth History Cardiac Caring Congenital Abnormality Data Defect Development Developmental Delay Disorders Diet Disease Embryo Embryonic Development Enzymes Family Future Genes Genetic Genetic Diseases Grant Habitual Abortion Human Inborn Errors of Metabolism Individual Kidney Knock-out Knockout Mice Kynurenine Kynurenine 3-monooxygenase Leadership Learning Disorders Limb structure Link Loss of Heterozygosity Mammals Measures Medicine Mentors Mentorship Metabolism Microcephaly Modeling Monitor Mus Neurocognitive Neurocognitive Deficit Nicotinamide adenine dinucleotide Nicotinic Acids Oral Organogenesis Pathway interactions Patients Phenotype Pregnancy Preventive Medicine Rare Diseases Reporting Resources Risk Role Serum Severities Site Supplementation Testing Training Translational Research Tryptophan Variant Weight Writing autism spectrum disorder career college congenital anomaly design dietary doctoral student genetic variant high risk human disease human model insight kynurenate loss of function microCT mother nutrition mouse model neurobehavioral neuropsychiatry novel parent grant personalized medicine postnatal postnatal development precision medicine preclinical study prenatal prevent rare genetic disorder skeletal skills spine bone structure translational scientist

项目摘要

ABSTRACT Recent studies have reported that genetic disruptions of the kynurenine pathway (KP) are a cause of congenital nicotinamide adenine dinucleotide (NAD) deficiencies in families with a history of birth defects and recurrent miscarriages. Mammals synthesize NAD+ from two different pathways. The KP biosynthesizes NAD+ de novo from dietary tryptophan, whereas the Preiss-Handler pathway utilizes dietary niacin. Birth defects associated with KP disruptions include phenotypes of vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies; some patients have developmental delay, learning disorders, autism, and/or microcephaly. Through the Undiagnosed Diseases Network site at Baylor College of Medicine (BCM), we have identified a patient with biallelic variants in the kynurenine 3-monooxygenase (KMO) gene, which encodes a key enzyme in the KP. The patient has congenital anomalies, short stature, and neurocognitive delays, representing a novel congenital NAD deficiency disorder (CNDD). In addition, she has extreme elevations in the serum levels of upstream metabolites (kynurenine and kynurenate). Dysregulation of these same metabolites have previously been linked to neuropsychiatric phenotypes in human patients with no obvious inborn errors of metabolism. Therefore, we hypothesize that KMO deficiency, a novel congenital NAD deficiency disorder, increases the risk for congenital anomalies and postnatal phenotypes, some of which are preventable with niacin supplementation. The Baylor College of Medicine (BCM) Center for Precision Medicine Models generates precision mouse models to support the discovery of novel undiagnosed disorders like KMO deficiency. These models serve as resources for additional pre-clinical studies investigating personalized and preventative medicine approaches to their care. Within the parent grant, we generated Kmo knockout (Kmo-/-) mice to explore the increased vulnerability of Kmo-/- embryos to congenital anomalies in the setting of low niacin diet. We will extend the studies in the parent grant to further characterize the prenatal and postnatal phenotypes associated with KMO deficiency and test whether niacin supplementation prevents the phenotypes. Thus, my proposed studies will demonstrate that biallelic loss-of-function variants in KMO cause a novel form of CNDD and demonstrate whether niacin supplementation prenatally or postnatally may prevent phenotypes associated with this new disorder. These findings will have the potential to benefit individuals with CNDD as well as provide insights into the role of NAD and kynurenine metabolism in normal prenatal and postnatal development.

抽象的最近的研究表明，犬尿氨酸通路 (KP) 的遗传破坏是导致有先天性缺陷家族史的先天性烟酰胺腺嘌呤二核苷酸（NAD）缺乏症和反复流产。哺乳动物通过两种不同的途径合成 NAD+。 KP 生物合成 NAD+ 从头开始从膳食色氨酸中提取，而 Preiss-Handler 途径则利用膳食烟酸。出生缺陷与 KP 破坏相关的表型包括椎骨、肛门、心脏、气管食管、肾和肢体异常；有些患者患有发育迟缓、学习障碍、自闭症和/或小头畸形。通过贝勒医学院 (BCM) 的未诊断疾病网络网站，我们发现了一种犬尿氨酸 3-单加氧酶 (KMO) 基因存在双等位基因变异的患者，该基因编码一种关键酶在金伯利进程中。该患者患有先天性异常、身材矮小和神经认知迟缓，这代表了一种新的症状。先天性 NAD 缺乏症 (CNDD)。此外，她的血清水平极度升高上游代谢物（犬尿氨酸和犬尿酸盐）。这些相同代谢物的失调以前曾发生过与没有明显先天性代谢缺陷的人类患者的神经精神表型有关。因此，我们假设 KMO 缺乏症（一种新型先天性 NAD 缺乏症）会增加先天性异常和产后表型的风险，其中一些可以通过烟酸预防补充。贝勒医学院 (BCM) 精准医学模型中心生成精密小鼠模型支持发现 KMO 缺乏症等新型未确诊疾病。这些模型可作为额外临床前研究的资源，调查个性化和预防性医学方法来治疗他们。在父母资助下，我们生成了 Kmo 敲除 (Kmo-/-) 小鼠探索低烟酸饮食环境下 Kmo-/- 胚胎对先天异常的脆弱性增加。我们将扩大父母资助的研究，以进一步表征产前和产后表型与 KMO 缺乏相关，并测试补充烟酸是否可以预防该表型。因此，我的拟议的研究将证明 KMO 中的双等位基因功能丧失变异会导致一种新形式的 CNDD 并证明产前或产后补充烟酸是否可以预防相关表型与这种新的疾病。这些发现将有可能使 CNDD 患者以及 CNDD 患者受益深入了解 NAD 和犬尿氨酸代谢在正常产前和产后的作用发展。