Development of a Commercial Platform for Discovery and Validation of Key Microbial Metabolites in CNS Disorders

开发用于发现和验证中枢神经系统疾病关键微生物代谢物的商业平台

基本信息

批准号：
9519227
负责人：
Shoko Iwai
金额：
$ 97.74万
依托单位：
SECOND GENOME, INC.
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：
2017-07-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9519227
关键词：
7 year old Address Adult Affect Age Alcoholism Animal Model Anxiety Area Award Back Basal Ganglia Behavior Bifidobacterium Brain Capital Cecum Cell Adhesion Molecules Central Nervous System Diseases Chemicals Child Clinical Clinical Data Clostridium Communication Communities Complex Computer Simulation Corpus striatum structure DNA Sequence Data Data Collection Dependence Development Diagnosis Diagnostic Disease Disease model Distant Drug Addiction Elements Environmental Risk Factor Etiology Evaluation Exhibits Family Family Study Feces First Degree Relative Functional disorder Funding Genes Genetic Genetic Predisposition to Disease Genome Goals Grant Heritability Human Microbiome Immunohistochemistry In Situ Individual Infrastructure Investigation Investments Knowledge Light Link Literature Locomotion Longitudinal cohort Measures Mediating Medical Metabolic Pathway Metagenomics Microbe Molecular Monitor Mus National Institute of Drug Abuse Nature Neuraxis Neurons Nucleic acid sequencing Online Systems Pathway interactions Peptides Performance Pharmacologic Substance Phase Phenotype Pilot Projects Play Predisposition Proteins Recombinant DNA Reporting Rewards Risk Risk Factors Role Sampling Services Ships Siblings Signal Pathway Small Business Innovation Research Grant Standardization Stereotyped Behavior Substance Addiction Substance Use Disorder Symptoms Synapses Synaptic Transmission System Technology Testing Therapeutic Time Validation Variant addiction autism spectrum disorder autistic children base clinically relevant cohort commensal bacteria cost design exome gene product genetic variant genomic data gut microbiome gut microbiota human subject in vivo machine learning algorithm metabolomics metatranscriptomics microbial microbial community microbiome mouse model neural circuit neural network neuropsychiatry novel novel therapeutic intervention pre-clinical preclinical efficacy predictive modeling recruit research and development stool sample therapeutic development therapeutic target trait

项目摘要

Despite a wealth of continued funding and ever emerging advancements in diagnostic and therapeutic technologies, the burden of central nervous system (CNS) disorders remains substantial. The cost of Substance Use Disorder (SUD) alone is estimated at > $181 billion (2002). The findings of numerous efforts tasked with identifying risk factors and causative agents of SUD suggest that vulnerability to dependence is a complex phenotype influenced by both genetics and environmental factors. Autism Spectrum Disorder (ASD) also appears to be largely impacted by both genetic and environmental factors, more specifically the gut microbiome. Recent studies have demonstrated that autism and SUD share common neural networks and molecular signaling pathways. Several of the gene-products associated with the ASD phenotype (e.g., synaptic cell adhesion molecules in the striatum and basal ganglia) affect synaptic transmission between neurons, which has also been implicated in the addiction and reward system. In addition, adults afflicted with high functioning autism exhibit greater susceptibility to drug dependence. We hypothesize that advancing the current state of knowledge regarding ASD, with particular regard to the attributes shared with drug addiction, will inspire the conceptualization and development of novel therapeutic interventions to correct common elements of striatal dysfunction. Testing this hypothesis will require a validated turn-key platform enabling customers the ability to ship clinical fecal samples from affected and unaffected subjects and receive a list of metabolites mediated by microbiome functions and a pre-clinical (in vivo) data package deciphering the phenotypic modulation of the CNS disease. With the funding received through this award, we will design, develop, and commercialize a robust CNS-microbiome-interplay (CMI) platform-based service that will enable (i) elucidation of novel microbiome-mediated targets in CNS diseases, including metabolites, proteins and peptides, (ii) pre-clinical data collection in standardized animal models, quantifying the influence of microbial bioactive molecules, and (iii) application across a wide range of therapeutic areas, such as SUD and ASD. The CMI platform-based service offering will allow medical and pharmaceutical pharma customers (i.e., our target market) to rapidly define diagnostic and therapeutic targets from clinical samples and deduce pre-clinical efficacy estimates sans investment in venture capital or complex infrastructure.

尽管有很多持续的资金，并且在诊断和治疗方面有了新兴的进步技术，中枢神经系统（CNS）疾病的负担仍然很大。用途的成本仅疾病（SUD）的估计估计超过1810亿美元（2002年）。为了识别风险的众多努力的调查结果 SUD的因素和因果剂表明，依赖性的脆弱性是受两者影响的复杂表型遗传学和环境因素。自闭症谱系障碍（ASD）似乎也受到两个遗传的影响和环境因素，更具体地说是肠道微生物组。最近的研究表明，自闭症和SUD共享共同的神经网络和分子信号传导途径。与ASD表型相关的几种基因产物（例如，突触细胞粘附分子纹状体和基底神经节）影响神经元之间的突触传播，这也与成瘾有关和奖励系统。此外，患有高功能自闭症的成年人对药物的敏感性更大依赖。我们假设促进有关ASD的当前知识状态，特别是与药物成瘾共享的属性，将激发新型治疗的概念化和发展干预措施以纠正纹状体功能障碍的常见元素。检验此假设将需要一个经过验证的交钥匙平台，使客户能够运送临床来自受影响和未受影响的受试者的粪便样本，并收到由微生物组功能介导的代谢物列表以及一个临床前（体内）数据包解解了中枢神经系统疾病的表型调节。有资金通过该奖项获得，我们将设计，开发和商业化强大的CNS-Microbiome-Interplay（CMI）基于平台的服务将使（i）阐明中枢神经系统疾病中新型微生物组介导的靶标代谢物，蛋白质和肽，（ii）标准化动物模型中的临床前数据收集，量化微生物生物活性分子的影响以及（iii）在广泛的治疗区域（例如SUD和）的影响 ASD。基于CMI平台的服务产品将允许医疗和制药客户（即我们的目标市场）迅速从临床样本中定义诊断和治疗靶标，并推断出临床前功效估计不投资风险投资或复杂的基础设施。