Mechanisms of Diabetic Susceptibility to Tuberculosis

糖尿病易患结核病的机制

• 批准号: 8932033
• 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/8932033
• 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; 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; macromolecule; macrophage; mycobacterial; non-diabetic; novel; novel strategies; prevent; rapid growth; receptor; receptor for advanced glycation endproducts; response; small hairpin RNA; small molecule; 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)：候选人布兰登·K·波德尔，DVM，正在寻求一个有指导的研究职业发展奖，以帮助他过渡到作为一名独立的生物医学研究人员的职业生涯。波德尔是一名兽医病理学家，他的职业目标是在学术教职上从事传染病和免疫学的研究，并将于2014年5月完成博士学位。波德尔博士制定了一项职业发展计划，该计划将促进结核病发病机制、结核病风险因素、 包括糖尿病，以及研究结核病和糖尿病的新治疗方法。专业人员将促进波德尔博士在先进的分子生物学、免疫学和蛋白质组学技术以及数据解释方面的发展。在新成立的咨询委员会中强调教师的批判性反馈、合作研究的发展以及在授予技巧和写作方面取得卓越成就的发展计划，将确保波德尔博士在获奖期间取得成功。波德尔博士将接受兰德尔·巴萨拉巴博士的指导。巴萨拉巴博士在结核病发病机制方面是一位有成就的研究人员，在糖尿病对结核病的易感性的建模和研究方面确立了自己的领导地位。结核病是一个对全球结核病控制具有重大影响的优先研究课题。糖尿病和结核病共病的研究是这一应用中拟议研究的重点，Basaraba博士代表了该机构最合适的导师。爱德华·胡佛博士将担任共同导师，并通过在研究、培训和众多K奖获得者方面指导兽医的丰富经验；他将支持波德尔博士向独立的过渡。CSU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一个出色的环境。糖尿病是结核病(TB)的一个公认的危险因素，然而，人们对这种共病的发病机制知之甚少。由于糖尿病在结核病发病率最高的发展中国家迅速增长，传染病和非传染性疾病的共同负担威胁着全球结核病控制。糖尿病的特征是无法控制的高血糖，这会加速糖对大分子的不受调节的修饰，导致晚期糖基化终产物(AGEs)的形成。AGEs通过RAGE受体诱导信号，促进促炎状态，RAGE受体是糖尿病相关并发症发生的潜在机制。由于(1)在我们的糖尿病-结核病共病动物模型中，高血糖与AGE的形成有关；(2)在这些模型中，高血糖诱导的AGE形成与炎症和病理增加相关；以及(3)在感染结核分枝杆菌(MTB)的糖尿病患者中，高血糖和相关的糖化与促炎细胞因子的增加有关，我们认为AGE的形成和RAGE信号导致促炎免疫反应，从而导致糖尿病患者患上更严重的肺结核。我们已经建立了第一个2型糖尿病豚鼠模型，也是唯一有效的2型糖尿病-结核病共病动物模型，这与人类对这种疾病知之甚少的复杂疾病显示出重要的相似之处。在目标1中，我们开发了一种新的策略来针对这种配体-受体相互作用，并确定年龄-RAGE信号是否会加重糖尿病豚鼠的结核病疾病。与合作者一起，我们开发了一种新型的、高度有效的抗衰老药物，将减少体内年龄的形成。RAGE受体将使用一种新近开发的高亲和力小分子抑制剂来靶向，该抑制剂被证明可以在体内阻止RAGE信号转导，并将在分离的天然豚鼠可溶性RAGE(SRAGE)的背景下进行解释，SRAGE是一种可溶受体亚型，可以隔离配体并阻止跨膜RAGE信号转导。通过这一策略，我们将确定年龄形成和/或RAGE信号是否与糖尿病患者中更严重的结核病有关。我们已经证明，与人类2型糖尿病相似，RAGE的表达与促炎细胞因子的表达类似，在糖尿病豚鼠中升高。在目标2中，我们将确定由于RAGE信号而产生的放大的先天免疫反应是否发生在结核分枝杆菌感染的早期，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，我们将在体内显示糖尿病豚鼠早期细胞因子反应的变化，并确定体外分离的肺泡巨噬细胞中RAGE介导的先天反应的放大是否损害了MTB感染的初始反应和控制。我们还表明，糖尿病豚鼠的获得性免疫反应延迟，这对控制结核分枝杆菌至关重要。由于早期的促炎反应损害了巨噬细胞的功能和适应性免疫的启动，并促进了破坏性炎症，在目标3中，我们将利用我科开发的新型肺内RNA干扰技术来研究RAGE和促炎条件对适应性免疫功能和损伤性炎症发生的影响。这些目标的成功完成将建立一种导致糖尿病患者结核病严重程度增加的新机制，我们将展示这种机制可以通过新的小分子进行靶向治疗。