Drug Discovery Today: Disease Models最新文献

The human body harbors trillions of commensal microbes which play a crucial role in host development of the immune system, gastrointestinal tract, and brain. An alteration in the composition or function of these microbes has been implicated in numerous neurological, neuropsychological, and gastrointestinal diseases. The germ-free rodent model, devoid of all microbes, has been increasingly used to uncover the microbial underpinnings of these diseases and to investigate potential therapeutic treatment options. This review describes the utility and limitations of this approach to assess microbiota-gut-brain axis. In particular we emphasize key differences in gross anatomy, neuroimmunity, the enteric nervous system, the blood brain barrier, gene expression, neurogenesis, myelination and behavior in the germ-free rodent model. Taken together, despite the lack of direct translational relevance the germ-free rodent has been a very useful tool to bolster knowledge of how microbes modulate brain and behavior.

Captive wildlife are a unique set of animals, whose diverse host–microbe symbioses are underexplored. Compared to their wild counterparts they are particularly susceptible to a variety of diseases, many of which have explicit or purported links to the microbiome. In this perspective, we will examine how the microbiome influences gastrointestinal disorders, metabolic dysregulation, reproduction, and disease susceptibility in captive wildlife. Investigation of wildlife, and specifically captive wildlife, affords a unique opportunity to gain understanding of the broad diversity of the associated microbiota and learn from nature’s molecular and microbial responses to disease. Studies like these could lead to the discovery of new interventions, ranging from dietary changes to the use of microbes or their natural products as treatment. Intervention strategies can lead to the discovery of medically relevant small molecules and the development of a novel platform for N-of-1 targeted medical investigations.

Ants have been widely studied, with 14,000 described species, but it is not until recently that they gained attention as sources for antimicrobial drug discovery. An increasing amount of studies are investigating ant-microbe symbioses, and clear benefits from their microbial counterparts have been experimentally demonstrated for ants in the tribes Attini, Camponotini and Cephalotini. The eusocial lifestyle of the insects, feeding on a wide variety of substrates, in some cases requires microbial symbionts to fight parasites. These microbes appear to be more active and less toxic than their traditionally explored soil counterparts, offering hope for our society’s fight against antimicrobial resistance.

Honey bee is used to model behavior, brain function, and life history transitions, and the physiology, genetics evolution, social behaviors have been intensively studied in this model organism. Recently, it shows that honeybees offer a particularly good opportunity to study the interactions between host biology and gut microbiota that are limited in complexity. All core members of the community are exclusive to this gut system, which are important to the host metabolism, endocrine signaling, and immune system as known in other animal-microbe symbioses. Like other comparatively simple insect model organisms that have been widely used for human disease, honey bees have the homologous or analogous organs, such as brain, fat body, oenocytes, gastrointestinal tract, and circulatory system, thus highlighting the bee a promising subject to model human diseases, in particular for understanding the role of microbiome in health and disease.

The nematode Caenorhabditis elegans is a key model system for experimental research on the genetic regulation of aging, and has paved the way towards many important discoveries in this field. Importantly, in the course of its short lifespan of ∼3 weeks, C. elegans displays many phenotypic, behavioral, and molecular changes that are widely shared among metazoans as they age. In this review, we summarize how aging research takes advantage of C. elegans’ biology, and we describe the experimental toolbox available to study worm aging.

Nothobranchius furzeri is an African killifish with an exceptionally short median life span of 3 to 7 months. Despite its short life span N. furzeri displays signs of aging that are highly reminiscent of mammalian aging. In 2015, reference sequences for the N. furzeri genome have been published. In addition, transgenesis and genomic engineering of killifish using CRISPR/Cas9 have been recently established. It has also been shown that N. furzeri is amenable to pharmacologic intervention. In this review we will discuss what makes N. furzeri a valuable model for research on aging and whether it could also be used for drug discovery.

The most robust interventions that impact on the biological processes of aging and age-related diseases are nutritional (caloric restriction, protein restriction, intermittent fasting) or those pharmacological and genetic interventions that act on nutrient sensing pathways. The best established nutritional intervention is caloric restriction, but this is not feasible in most humans; therefore, other nutritional interventions that influence aging but do not involve protracted periods of fasting have been studied. The Geometric Framework provides a powerful research tool for disentangling the effects of various nutrients and calorie intake, in both restricted and ad libitum-fed diets, on phenotypic outcomes such as aging and lifespan. This approach can also be applied to understanding the complex network of nutrient sensing pathways, potentially identifying new targets for the development of drugs that influence healthy aging.

Advanced computational approaches are needed to interpret the data generated by high-throughput molecular profiling methods. This necessity is particularly pressing in the field of aging research because (i) it is challenging to separate causes and consequences of aging, (ii) samples are often very precious, thus reducing the number of biological replicates, and (iii) heterogeneity between replicates can be particularly high at old age. Here, we describe computational approaches ranging from basic data processing up to the integration of heterogeneous data types. For future studies, we suggest to sample more time points and -omics layers, and to determine to what extent reference information from young animals can be transferred to old ones in data integration approaches.

With the advancing age of humans and with it, growing numbers of age-related diseases, aging has become a major focus in recent research. The lack of fitting aging models, especially in neurological diseases where access to human brain samples is limited, has highlighted direct conversion into induced neurons (iN) as an important method to overcome this challenge. Contrary to iPSC reprogramming and its corresponding cell rejuvenation, the generation of iNs enables us to retain aging signatures throughout the conversion process and beyond. In this review, we explore different cell reprogramming methods in light of age-associated neurodegenerative diseases and discuss different approaches, advances, and limitations.