Fatty Acid Metabolism's Role in M.tuberculosis virulence

脂肪酸代谢在结核分枝杆菌毒力中的作用

基本信息

批准号：
7578222
负责人：
Issar SMITH
金额：
$ 36.28万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-15 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): What specific traits of M. tuberculosis (Mtb) are essential for its survival in its infected mammalian hosts? This question can be phrased more specifically: Does Mtb's metabolism change during the course of infection to allow it to persist for long periods during the chronic phase of infections? Previous studies performed in various laboratories including the PI's have shown that many Mtb genes encoding enzymes involved in fatty acid metabolism are upregulated during infections of human macrophages and mice. This information combined with much data in the old and more recent literature suggest a major role for this process in Mtb virulence and that it could provide potential targets for new therapies and diagnostics for TB. This research proposal will study the genetics, biochemistry and physiology of fatty acid metabolism, concentrating on fatty acid degradation and transport, as well as regulators for these and related processes. The rationale for this proposal is that an understanding of the mechanisms of Mtb fatty acid metabolism and how this is important for pathogenesis will be essential for the designing of anti-tubercular strategies that will use components of this process as targets. The aims of the proposal are: I) Specific genes annotated to encode enzymes involved in fatty acid metabolism and their regulators will be identified by a series of approaches and then they will be inactivated; II) The role of these genes and the enzymes/proteins they encode in Mtb virulence will be tested by analyzing the growth and pathogenicity of the mutants in macrophages and mice; III) The function of these genes and the enzymes they encode that are found to be important for M. tuberculosis virulence, as described in specific aim II, will be characterized by purifying the proteins they encode and biochemically assaying the function of the proteins. Other fatty acid metabolic enzymes will also be characterized, even though they may not be essential for pathogenicity as this will provide useful information on Mtb physiology.

描述（由申请人提供）：结核分枝杆菌（MTB）的哪些特定特征对于其在感染的哺乳动物宿主中生存至关重要？这个问题可以更具体地表达：MTB在感染过程中的新陈代谢会改变以使其在感染的慢性阶段长期持续存在吗？先前在包括PI在内的各种实验室进行的研究表明，在人类巨噬细胞和小鼠的感染过程中，许多编码参与脂肪酸代谢酶的MTB基因都上调。这些信息与旧文献中的大量数据相结合，这表明该过程在MTB毒力中起着重要作用，并且可以为TB提供新的疗法和诊断的潜在靶标。该研究建议将研究脂肪酸代谢的遗传学，生物化学和生理学，集中于脂肪酸降解和运输，以及这些和相关过程的调节剂。该提案的理由是，了解MTB脂肪酸代谢的机制以及对发病机理的重要性对于设计将使用该过程的组成部分的抗结核策略至关重要。该提案的目的是：i）注释的特定基因编码参与脂肪酸代谢的酶，其调节剂将通过一系列方法来识别，然后它们将被灭活； ii）这些基因和它们在MTB毒力中编码的酶/蛋白质的作用将通过分析巨噬细胞和小鼠突变体的生长和致病性来测试； iii）这些基因的功能及其编码的酶，这些酶对结核分枝杆菌的毒力很重要，如特定目标II中所述，将以净化其编码的蛋白质并在生化上分析蛋白质功能的特征。即使它们对致病性并不重要，因此其他脂肪酸代谢酶也会被表征，因为这将提供有关MTB生理学的有用信息。