Mechanisms of Diabetic Susceptibility to Tuberculosis

糖尿病易患结核病的机制

• 批准号: 9090204
• 负责人: Brendan Podell
• 金额: $ 12.31万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090204
• 关键词: Accounting; Achievement; Address; Advanced Glycosylation End Products; Advisory Committees; Affinity; Alveolar Macrophages; Animal Model; Antigens; Area; Award; Bronchoalveolar Lavage; Cavia; Cells; Cellular Immunity; Characteristics; Chemicals; Clinical Data; Clinical Research; Communicable Diseases; Comorbidity; Complex; Complications of Diabetes Mellitus; Country; Data; Data Analyses; Developing Countries; Development; Development Plans; Diabetes Mellitus; Disease; Doctor of Philosophy; Ensure; Environment; Epidemic; Event; Faculty; Feedback; Goals; Growth; Health; Human; Hyperglycemia; Immune; Immune response; Immunity; Immunology; Incidence; Infection; Infectious Disease Immunology; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Institution; Interleukin-12; Interleukin-17; Interleukin-6; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Laboratory Research; Lead; Ligands; Link; Measures; Mediating; Mentors; Methods; Modeling; Modification; Molecular Biology; Mycobacterium tuberculosis; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathologist; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predisposition; Prevalence; Production; Protein Isoforms; Proteomics; RNA Interference; Receptor Signaling; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; Severities; Signal Transduction; Study models; T-Cell Depletion; T-Lymphocyte; Techniques; Testing; Th1 Cells; Tissues; Tuberculosis; Veterinarians; Writing; adaptive immunity; career; career development; cytokine; diabetes control; diabetic; disorder control; experience; glycation; immune function; in vivo; inhibitor/antagonist; knock-down; macromolecule; macrophage; mycobacterial; non-diabetic; novel; novel strategies; prevent; rapid growth; receptor; receptor for advanced glycation endproducts; response; small hairpin RNA; small molecule; small molecule inhibitor; success; sugar

DESCRIPTION (provided by applicant): The candidate, Brendan K. Podell, DVM, is pursuing a mentored research career development award to aid in his transition into a career as an independent biomedical researcher. Dr. Podell is a veterinary pathologist with career goals of pursuing research in infectious disease and immunology in an academic faculty position and will complete a PhD degree in May of 2014. Dr. Podell has established a career development plan that will facilitate a research career in tuberculosis pathogenesis, risk factors for tuberculosis, including diabetes, and investigation of novel treatment methods for both tuberculosis and diabetes. Expert faculty will facilitate Dr. Podell's development in advanced molecular biology, immunology and proteomic techniques and data interpretation. A development plan that emphasizes critical feedback from faculty in a newly established advisory committee, development of collaborative research, and achievement of excellence in grantsmanship and writing will ensure Dr. Podell's success during the award period. Dr. Podell will be mentored by Dr. Randall Basaraba, who is an accomplished researcher in tuberculosis pathogenesis and has established himself as a leader in the modeling and study of diabetic susceptibility to tuberculosis, a prioritized research topic with major impact on global tuberculosis control. The study of diabetes-tuberculosis comorbidity is the focus of the proposed research in this application and Dr. Basaraba represents the best-suited mentor at this institution. Dr. Edward Hoover will serve as co-mentor and through extensive experience mentoring veterinarians in research training and numerous K-awardees; he will support Dr. Podell's transition to independence. The CSU Mycobacterial Research Laboratories, a network of 21 internationally recognized investigators in mycobacterial disease, will provide an outstanding environment for development of the candidate. Diabetes is an established risk factor for tuberculosis (TB), however little is known about the pathogenesis of this comorbidity. Due to the rapidly growing prevalence of diabetes in developing countries with the highest incidence of TB, this combined burden of communicable and non-communicable diseases threatens global TB control. Diabetes is characterized by uncontrolled hyperglycemia, which accelerates the unregulated modification of macromolecules by sugars leading to the formation of advanced glycation end products (AGEs). AGEs promote a pro-inflammatory state by inducing signaling through the RAGE receptor, an underlying mechanism for development of diabetes-related complications. Since (1) hyperglycemia is linked to AGE formation in our animal models of DM-TB comorbidity; (2) hyperglycemia-induced AGE formation is associated with increased inflammation and pathology in these models; and (3) poorly controlled hyperglycemia and related glycation are associated with increased pro-inflammatory cytokines in Mycobacterium tuberculosis (Mtb) infected diabetic humans, we propose that AGE formation and RAGE signaling lead to a pro-inflammatory immune response that dictates more severe TB in diabetics. We have developed the first guinea pig model of type 2 diabetes and the only validated animal model of type 2 diabetes-tuberculosis comorbidity, which shows important similarities to what little is known about this disease complex in humans. In Aim 1, we have developed a novel strategy to target this ligand-receptor interaction and determine if AGE-RAGE signaling worsens TB disease in diabetic guinea pigs. Along with collaborators, we have developed a novel and highly potent class of anti-AGE drugs that will reduce AGE formation in vivo. The RAGE receptor will be targeted using a recently developed, high affinity small molecule inhibitor proven to prevent RAGE signaling in vivo and will be interpreted in the context of isolated native guinea pig soluble RAGE (sRAGE), a soluble receptor isoform that sequesters ligands and prevents transmembrane RAGE signaling. Through this strategy, we will determine if AGE formation and/or RAGE signaling are responsible for more severe TB in diabetics. We have shown that RAGE expression along with pro-inflammatory cytokine expression, similar to humans with type 2 diabetes, are elevated in diabetic guinea pigs. In Aim 2, we will determine if an amplified innate immune response due to RAGE signaling occurs early in Mtb infection and impairs the ability to control bacterial growth. Through use of the small molecule RAGE inhibitor and RNA interference, we will demonstrate alterations in the early cytokine response in vivo in diabetic guinea pigs as well as determine if the initial response and control of Mtb infection is impaired by RAGE-mediated amplification of the innate response in ex vivo isolated alveolar macrophages. We have also shown that diabetic guinea pigs have a delay in the adaptive immune response that is critical for control of Mtb. Since an early pro-inflammatory response impairs macrophage function and priming of adaptive immunity, and promotes destructive inflammation, in Aim 3, we will investigate the impact of RAGE and pro-inflammatory conditions on onset of adaptive immune function and damaging inflammation using novel intrapulmonary RNA interference techniques developed in our department. Successful completion of these aims will establish a novel mechanism responsible for heightened severity of TB in diabetics, which we will show can be targeted therapeutically with novel small molecules.

描述（由申请人提供）：候选人 Brendan K. Podell，DVM，正在寻求指导研究职业发展奖，以帮助他过渡到独立生物医学研究员的职业生涯。 Podell 博士是一名兽医病理学家，其职业目标是在学术教职职位上从事传染病和免疫学研究，并将于 2014 年 5 月完成博士学位。 Podell 博士制定了职业发展计划，该计划将促进结核病发病机制、结核病危险因素、 包括糖尿病，以及结核病和糖尿病新治疗方法的研究。专家团队将促进 Podell 博士在先进分子生物学、免疫学和蛋白质组学技术以及数据解释方面的发展。一项发展计划强调新成立的咨询委员会中教师的关键反馈、合作研究的发展以及在资助和写作方面取得的卓越成就，这将确保波德尔博士在获奖期间取得成功。 Podell 博士将得到 Randall Basaraba 博士的指导，Randall Basaraba 博士是结核病发病机制方面一位卓有成就的研究员，并已成为糖尿病对结核病易感性建模和研究的领导者，这是一个对全球结核病控制产生重大影响的优先研究课题。糖尿病-结核病合并症的研究是本申请中拟议研究的重点，巴萨拉巴博士是该机构最合适的导师。爱德华·胡佛博士将担任联合导师，并通过丰富的经验指导兽医进行研究培训和众多 K 奖获得者；他将支持波德尔博士向独立过渡。科罗拉多州立大学分枝杆菌研究实验室是一个由 21 名国际公认的分枝杆菌疾病研究人员组成的网络，将为候选人的发展提供良好的环境。糖尿病是结核病 (TB) 的一个确定的危险因素，但人们对这种合并症的发病机制知之甚少。由于结核病发病率最高的发展中国家糖尿病患病率迅速上升，这种传染病和非传染性疾病的综合负担威胁着全球结核病控制。糖尿病的特点是不受控制的高血糖，它加速了糖对大分子的不受调节的修饰，导致晚期糖基化终末产物 (AGE) 的形成。 AGEs 通过 RAGE 受体诱导信号传导来促进促炎症状态，RAGE 受体是糖尿病相关并发症发生的潜在机制。因为 (1) 在我们的 DM-TB 合并症动物模型中，高血糖与 AGE 形成有关； (2) 在这些模型中，高血糖诱导的 AGE 形成与炎症和病理的增加有关； (3) 控制不良的高血糖和相关糖化与结核分枝杆菌 (Mtb) 感染的糖尿病人中促炎细胞因子的增加有关，我们认为 AGE 形成和 RAGE 信号传导会导致促炎免疫反应，从而导致糖尿病患者出现更严重的结核病。我们开发了第一个 2 型糖尿病豚鼠模型，也是唯一经过验证的 2 型糖尿病-结核病合并症动物模型，该模型与人类对这种疾病复合物知之甚少有重要相似之处。在目标 1 中，我们开发了一种新策略来靶向这种配体-受体相互作用，并确定 AGE-RAGE 信号传导是否会恶化糖尿病豚鼠的结核病。我们与合作者一起开发了一种新型且高效的抗 AGE 药物，可以减少体内 AGE 的形成。 RAGE 受体将使用最近开发的高亲和力小分子抑制剂来靶向，该抑制剂已被证明可以在体内阻止 RAGE 信号传导，并将在分离的天然豚鼠可溶性 RAGE (sRAGE) 的背景下进行解释，sRAGE 是一种可溶性受体亚型，可隔离配体并防止跨膜 RAGE 信号传导。通过这一策略，我们将确定 AGE 形成和/或 RAGE 信号传导是否导致糖尿病患者出现更严重的结核病。我们发现，与患有 2 型糖尿病的人类相似，糖尿病豚鼠中的 RAGE 表达以及促炎细胞因子表达均升高。在目标 2 中，我们将确定 RAGE 信号传导导致的先天免疫反应是否会在 Mtb 感染早期发生，并损害控制细菌生长的能力。通过使用小分子 RAGE 抑制剂和 RNA 干扰，我们将证明糖尿病豚鼠体内早期细胞因子反应的改变，并确定离体分离的肺泡巨噬细胞中 RAGE 介导的先天反应放大是否会损害 Mtb 感染的初始反应和控制。我们还表明，糖尿病豚鼠的适应性免疫反应存在延迟，这对于控制结核分枝杆菌至关重要。由于早期的促炎反应会损害巨噬细胞功能和适应性免疫的启动，并促进破坏性炎症，因此在目标 3 中，我们将使用我们部门开发的新型肺内 RNA 干扰技术来研究 RAGE 和促炎条件对适应性免疫功能和破坏性炎症的影响。成功完成这些目标将建立一种导致糖尿病患者结核病严重程度升高的新机制，我们将证明可以用新型小分子进行靶向治疗。