Systematic discovery of nonobvious human disease models by orthologous phenotypes

描述(申请人提供)：系统生物学方法在更好地了解人类疾病和确定新的疾病靶点方面显示出巨大的前景。尽管如此，在大多数遗传性疾病中识别原因基因仍然非常困难，特别是高度多基因疾病，目前的方法对这些疾病的研究非常有限。一旦确定了目标，这些方法通常也会停止，进一步的研究将过渡到传统的药物发现范式。我们假设(‘表型’假说)，在人类和模式生物中识别等同的基因网络将揭示新的候选疾病基因和新的疾病模式系统。此外，这样的模型可以导致基于模式生物中的网络进行药物发现的可能性。我们认为，由于通路可以在不同的生物体中进化和改变用途，因此可能存在物候素，但产生不同表型的相似(或同源)基因网络可能存在，并且这些物候素不仅为针对单一蛋白质的筛选提供了基础，而且还为识别和同时针对多个不同靶点的药物发现工作提供了基础。作为评价途径进化再利用的重要性的一个例子，我们确定了一个血管生成的酵母模型，以及它随后在疾病基因和药物发现中的应用。同样的理论框架提出了自闭症的小鼠模型、乳腺癌的蠕虫模型等。我们的主要目标是验证表型假说，主要使用酵母模型来发现新的血管生成基因&进行基于酵母的化合物筛选，以发现新的抗血管生成抑制剂，适合作为抗癌治疗的先导化合物。物候学提供了将新基因与多基因疾病联系起来的可能性，并在模式生物中开辟了药物筛选和后续研究，寻找候选疾病基因的遗传变异。因此，理论物候学框架有可能影响多种疾病，并可能潜在地影响一个大的下游社区。

DESCRIPTION (provided by applicant): Systems biology methods have shown great promise in providing a better understanding of human disease, and in identifying new disease targets. Nonetheless, it remains extraordinarily difficult to identify causal genes in most genetic diseases, in particular highly polygenic disorders, for which current approaches are most limited. These methods also typically leave off once the target is identified, and further research transitions to traditional paradigms for drug discovery. We hypothesize (the 'phenolog' hypothesis) that the identification of equivalent gene networks in humans and model organisms will reveal new candidate disease genes and new model systems for diseases. Moreover, such models can lead to the possibility of pursuing drug discovery based on the networks in the model organisms. We suggest that because pathways can evolve and be repurposed in different organisms that phenologs, similar (or orthologous) gene networks that nonetheless produce different phenotypes, may be present, and that these phenologs provide a basis not just for screening against a single protein, but rather for the identification of and simultaneous drug discovery efforts against multiple different targets in parallel. As an example of the importance of appreciating the evolutionary repurposing of pathways, we identify a yeast model of angiogenesis, and its subsequent application to disease gene and drug discovery. The same theoretical framework suggests a mouse model of autism, a worm model of breast cancer, and more. Our major aim is to test the phenolog hypothesis, primarily using the yeast model to discover new angiogenesis genes & performing yeast-based compound screening to find new classes of anti-angiogenesis inhibitors, suitable as lead compounds for anti-cancer therapies. Phenologs offer the possibility of associating new genes with polygenic diseases, as well as opening up drug screens in model organisms and follow-up studies searching for genetic variation in the candidate disease genes. The theoretical phenolog framework thus has the potential to impact a wide variety of diseases and could potentially affect a large downstream community.