Master regulators of unexplained variation in disease risk

疾病风险无法解释的变异的主要调节因素

• 批准号: 10670982
• 负责人: JOSEPH H. NADEAU
• 金额: $ 192.26万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670982
• 关键词: Address; Animal Model; Architecture; Area; Atlases; Biological; Biological Models; Biomedical Research; Catalogs; Chromosomes; Communities; Complex; Data; Databases; Development; Diagnosis; Diagnostic; Dimensions; Disease; Diseases in Twins; Elderly; Environment; Epigenetic Process; Etiology; Gene Activation; Gene Expression; Gene Silencing; Genes; Genetic; Genome; Genotype; Heterogeneity; Human; Human Genetics; Inbreeding; Individual; International; Knowledge; Lead; Link; Mainstreaming; Measures; Medicine; Metabolic; Methods; Molecular; Monozygotic twins; Mus; Neurologic; Organism; Outcome; Persons; Phenotype; Phylogenetic Analysis; Physiological; Population; Precision Medicine Initiative; Process; Property; Protocols documentation; Quantitative Trait Loci; Regulator Genes; Reporting; Science; Seminal; Standardization; Surveys; Testing; Therapeutic Intervention; Variant; Vertebrates; Work; biological systems; cohort; data resource; disease heterogeneity; disorder risk; driving force; genome-wide; human disease; innovation; insight; interest; non-genetic; precision medicine; trait

PROJECT SUMMARY Precision medicine requires an understanding of the origins and molecular control over complex traits and disease. The field is largely driven by human genetics, which adheres to a 1918 dogma that phenotype is determined solely by genetics and the environment. Yet, evidence from monozygotic twins and isogenic animal models indicate that up to 50% of phenotypic variation across diverse physiological traits and diseases cannot be explained by genetics or environment – there is something `more' that is unique to each individual, and that cannot be determined by analyzing population-level mean effects. These findings also indicate that even if we did have `complete' genetic and environmental knowledge, a substantial portion of disease heterogeneity would remain unaccounted for. The operating hypothesis for this project is that a substantial fraction of unexplained disease heterogeneity reflects inherently probabilistic properties of the biological system that lead to fixed, deterministic, real biological variation. There is compelling evidence for an evolved molecular circuitry that controls phenotypic variability as a quantitative trait. Thus, understanding variability as a quantitative trait is essential to understanding the etiology of phenotypic diversity (in general) and an individual's disease potential (in particular). Here, we will begin to finally answer the precision medicine questions of: what is the normal or expected disease potential for me? And, what are the origins and regulatory controls of non-genetic, non- environmental phenotypic and disease variability in humans? The first steps towards addressing these questions and identifying mechanisms through which probabilistic processes lead to disease heterogeneity is to create a catalogue of putative variance regulators and genes; a phenotypic, epigenetic, and cellular variance atlas charting the landscape of probabilistic variation in an isogenic model system (mice); and, to demonstrate that the regulatory architecture of variance control is conserved between mouse and humans. If it is true that a significant portion of unexplained disease heterogeneity is due to the molecular control of variability itself, then we will have uncovered an entirely new area of disease etiology that can be harnessed by the community to develop fundamentally new predictive, diagnostic, and therapeutic interventions, irrespective of the disease of interest.

项目总结 精确医学需要了解复杂性状的起源和分子控制 疾病。这个领域在很大程度上是由人类遗传学驱动的，人类遗传学坚持1918年的一种教条，即表型是 完全由遗传和环境决定。然而，来自同卵双胞胎和同基因动物的证据 模型表明，高达50%的不同生理性状和疾病的表型变异不能 用遗传学或环境来解释--每个人都有一些独一无二的东西，而且 不能通过分析人口水平的平均效应来确定。这些发现还表明，即使我们 如果对遗传和环境有“完整”的了解，很大一部分疾病的异质性 仍然下落不明。这个项目的运作假设是，有很大一部分未解释的 疾病异质性内在地反映了生物系统的概率属性，这些属性导致固定的、 确定性的，真正的生物变异。有令人信服的证据表明，进化的分子电路 将表型变异作为数量性状进行控制。因此，将变异性理解为数量性状是 了解表型多样性的病因学(一般)和个体的疾病潜在性 (特别是)。在这里，我们将开始最终回答精准医学的问题：什么是正常的或 对我来说有潜在的疾病吗？那么，非遗传性、非遗传性和非遗传性的 人类的环境表型和疾病变异性？解决这些问题的第一步 确定概率过程导致疾病异质性的机制是创建一个 假定的变异调节因子和基因目录；表型、表观遗传和细胞变异图谱 绘制等基因模型系统(老鼠)中概率变异的图景；以及，为了证明 方差控制的调控架构在老鼠和人类之间是保守的。如果这是真的， 无法解释的疾病异质性的很大一部分是由于变异性本身的分子控制，那么 我们将发现一个全新的疾病病因学领域，社区可以利用这个领域来 开发全新的预测性、诊断性和治疗性干预措施，不受疾病的影响 利息。

项目成果

A rapid microglial metabolic response controls metabolism and improves memory.

快速的小胶质细胞代谢反应控制新陈代谢并提高记忆力。

• DOI: 10.1101/2023.04.03.535373
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Drougard,Anne;Ma,EricH;Wegert,Vanessa;Sheldon,Ryan;Panzeri,Ilaria;Vatsa,Naman;Apostle,Stefanos;Fagnocchi,Luca;Schaf,Judith;Gossens,Klaus;Völker,Josephine;Pang,Shengru;Bremser,Anna;Dror,Erez;Giacona,Francesca;Sagar;Henderson
• 通讯作者: Henderson

Independent phenotypic plasticity axes define distinct obesity sub-types.

• DOI: 10.1038/s42255-022-00629-2
• 发表时间: 2022-09
• 期刊: NATURE METABOLISM
• 影响因子: 20.8
• 作者: Yang, Chih-Hsiang;Fagnocchi, Luca;Apostle, Stefanos;Wegert, Vanessa;Casani-Galdon, Salvador;Landgraf, Kathrin;Panzeri, Ilaria;Dror, Erez;Heyne, Steffen;Woerpel, Till;Chandler, Darrell P.;Lu, Di;Yang, Tao;Gibbons, Elizabeth;Guerreiro, Rita;Bras, Jose;Thomasen, Martin;Grunnet, Louise G.;Vaag, Allan A.;Gillberg, Linn;Grundberg, Elin;Conesa, Ana;Korner, Antje;Pospisilik, J. Andrew
• 通讯作者: Pospisilik, J. Andrew

The DECON pilot project investigates predictive markers for successful bariatric surgery.

• DOI: 10.1038/s41598-023-40452-7
• 发表时间: 2023-08-17
• 期刊: Scientific reports
• 影响因子: 4.6