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; 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，DVM的Brendan K. Podell正在寻求指导的研究职业发展奖，以帮助他过渡到作为独立生物医学研究人员的职业。 Podell博士是一名兽医病理学家，其职业目标是在学术教师职位上追求传染病和免疫学研究，并将在2014年5月完成博士学位。Podell博士制定了一项职业发展计划，该计划将促进结核病病原体，结核病，结核病，结核病的风险因素，危险。 包括糖尿病以及结核病和糖尿病的新型治疗方法的研究。专家教师将促进Podell博士在高级分子生物学，免疫学和蛋白质组学技术和数据解释方面的发展。一项开发计划，强调了新成立的咨询委员会，合作研究的发展以及实现授予技巧和写作卓越的重要反馈，将确保Podell博士在奖励期间的成功。 Podell博士将由Randall Basaraba博士进行指导，Randall Basaraba博士是一位有成就的结核病发病机理研究人员，并已确立了对糖尿病易感性结核病的建模和研究的领导者，这是对全球结核病控制的重大影响的优先研究主题。糖尿病 - 结核病合并症的研究是该应用程序中提议的研究的重点，巴萨拉巴博士代表了该机构最适合的导师。爱德华·胡佛（Edward Hoover）博士将通过领导研究培训的兽医和众多k-awardees的丰富经验。他将支持Podell博士向独立的过渡。 CSU分枝杆菌研究实验室是由21个国际认可的分枝杆菌疾病的研究人员组成的网络，将为候选人的发展提供一个杰出的环境。糖尿病是结核病（TB）的确定危险因素，但是对这种合并症的发病机理知之甚少。由于结核病发病率最高的发展中国家糖尿病患病率迅速增长，这种传染性和非传染性疾病的总负担威胁到全球结核病的控制。糖尿病的特征是不受控制的高血糖，这加速了通过糖对大分子对大分子的不受调节的修饰，从而导致高级糖基化终产物（AGES）形成。年龄通过通过RAGE受体诱导信号传导来促进促炎状态，这是一种与糖尿病相关并发症发展的潜在机制。由于（1）高血糖与我们的DM-TB合并症动物模型中的年龄形成有关； （2）高血糖引起的年龄形成与这些模型中的炎症和病理增加有关； （3）控制不良的高血糖和相关糖基化与感染糖尿病性人体的结核分枝杆菌（MTB）感染的糖尿病患者的促炎性细胞因子有关，我们提出年龄形成和愤怒信号导致促疾病的促炎免疫反应，这决定了糖尿病中更严重的TB的严重TB。我们已经开发了第一个2型糖尿病的豚鼠模型，以及唯一经过验证的2型糖尿病 - 糖尿病的动物模型合并症，这表明与人类对这种疾病复合物知之甚少的相似之处。在AIM 1中，我们制定了一种新的策略来瞄准这种配体 - 受体相互作用，并确定年龄段信号是否会使糖尿病豚鼠中的结核病疾病恶化。与合作者一起，我们开发了一种新颖且高度强大的抗衰老药物，可以减少体内年龄形成。愤怒受体将使用最近开发的高亲和力小分子抑制剂进行靶向，该抑制剂被证明可以防止体内愤怒的信号传导，并将在孤立的天然豚鼠可溶性愤怒（Srage）的背景下进行解释，这是一种可溶性受体同工型，这是一种隔离的，可隔离的，可隔离，可隔离并阻止透射膜rage rage信号。通过这种策略，我们将确定年龄形成和/或愤怒信号是否导致糖尿病患者更严重的结核病。我们已经表明，在糖尿病豚鼠中，愤怒的表达和促炎性细胞因子表达与2型糖尿病的人相似。在AIM 2中，我们将确定在MTB感染的早期发生愤怒信号引起的放大先天免疫反应，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的体内细胞因子反应的改变，并确定MTB感染的初始反应和控制是否会因rage介导的rage介导的液体介导的生物分离的肺泡摩尔噬细胞的rage介导的扩增而受损。我们还表明，糖尿病豚鼠的适应性免疫反应延迟，这对于控制MTB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，在AIM 3中，我们将研究愤怒和促炎条件对适应性免疫功能的发作的影响，并使用新型部门开发的新型RNA干扰技术损害炎症，并损害炎症。这些目标的成功完成将建立一种新的机制，负责增加糖尿病患者结核病的严重程度，我们将证明可以用新型的小分子对其进行治疗。