Mapping the road to recovery - Does the way we get better differ from the way we

描述 摘要： 我假设，从感染中恢复是一个积极的过程，不同于我们从健康中获得的途径 对于病理学，我想了解是什么特性使患者对感染具有弹性。换句话说，如何 我们生病了，然后又康复了吗？ 我的目标是修复我们在实验室中研究的微生物发病机制与我们在 治疗感染病人。作为研究感染的科学家，我们主要定义控制机制 一个宿主病得有多重。我们的哲学是，如果我们能防止人们变得极端 生病了。不幸的是，这意味着我们很擅长定义病人的病情 他们出现在急诊室；我们让医生来清除感染，让患者恢复健康 州政府。恢复健康的途径可能涉及定义疾病途径的相同生理机制 但它可能不会；我们不知道，因为我们不研究复苏。 我正在提出一个研究宿主-微生物相互作用的新范式，在这个范式中，我们使用整个动物来定义 管理恢复(疾病恢复的路线)和弹性(主机的能力)的属性 被干扰，然后返回到其原始状态)。我将确定指导复苏的基本原则和 建立一个概念框架，在这个框架中可以继续研究这一被忽视但很重要的疾病阶段。我 我将用以下三个目的来剖析这个问题。 目标1：测试已知的决定下降的机制是否参与了复苏。 已知的耐药性和耐受性机制将被测试它们在从细菌感染中恢复的作用。 这将有助于描述控制恢复曲线形状的属性。 目标2：确定参与恢复的新机制。 我们将对感染后恢复能力改变的突变进行正向基因筛查。这将是 通过问一个关于康复需要什么的开放问题来引导我们走向新生物学，而不是问 “恢复是否需要‘进程X’？” 目标3：开发一个预测系统级别的复原力模型。 我们将使用数学模型来定义具有弹性的系统，这些系统要么是健康的，要么是持续感染的 或促炎状态，然后使用前两个目标中开发的工具测试这些模型。

DESCRIPTION Abstract: I hypothesize that recovery from infection is an active process that differs from the route we take from health to pathology; I want to understand what properties make patients resilient to infections. In other words, how do we get sick AND recover? My goal is to repair the dissonance between microbial pathogenesis as we study it in the lab and the way we treat patients with infections. As scientists studying infections we mostly define the mechanisms controlling how sick a host gets. The philosophy is that we can help people if we can prevent them from getting extremely ill. Unfortunately, what this means is that we are great at defining just how sick a patient will be when they show up in the ER; we leave it to the physician to clear the infection and return the patient to a healthy state. The route back to health may involve the same physiological mechanisms that define the route to sickness but it may not; we don’t know because we don’t study recovery. I am proposing a new paradigm for studying host-microbe interactions where we use whole animals to define the properties governing recovery (the route back from sickness) and resilience (the ability of the host to be perturbed and then return to its original state). I will identify fundamental principles governing recovery and to establish a conceptual framework in which this neglected but important phase of disease can be pursued. I will use the following three aims to dissect this problem. Aim 1: Test if mechanisms known to dictate decline are involved in recovery. Known resistance and tolerance mechanisms will be tested for their role in recovering from bacterial infections. This will help describe the attributes that control the shape of a recovery curve. Aim 2: Identify novel mechanisms involved in recovery. We will perform a forward genetic screen for mutants with altered ability to recover from infections. This will lead us towards new biology by asking an open question about what is required for recovery rather than asking “is ‘process X’ required for recovery?” Aim 3: Develop a predictive systems-level model of resilience. We will use mathematical models to define resilient systems that are either healthy or stuck in persistent infections or pro-inflammatory states and then test these models using the tools developed in the first two aims.