Genetics, glycemic control and the microbiome in cystic fibrosis

囊性纤维化的遗传学、血糖控制和微生物组

• 批准号: 10264820
• 负责人: Laura N Brenner
• 金额: $ 19.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264820
• 关键词: Adult; Affect; Age; Antibiotics; Artificial Pancreas; Beta Cell; Biodiversity; Bionics; Blood Glucose; Body mass index; Carbohydrates; Caring; Cell physiology; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Communities; Complex; Complication; Coupled; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Devices; Diabetes Mellitus; Diagnosis; Disease; Enrollment; Ethnic Origin; Etiology; European; Family; Feces; Funding; Genetic; Genetic Determinism; Glucagon; Glucose; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intake; Intervention; Investigation; Life; Life Expectancy; Linear Regressions; Link; Lung; Lung infections; Measures; Mediating; Mediation; Medical Genetics; Mendelian randomization; Mentors; Methods; Microbe; Microbial Taxonomy; Modeling; Modification; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Outcome; Pancreas; Patients; Pattern; Pseudomonas aeruginosa; Pulmonary Function Test/Forced Expiratory Volume 1; Quality of life; Randomized; Randomized Clinical Trials; Recording of previous events; Research; Resistance; Risk; Sampling; Serum; Shotguns; Sputum; Staphylococcus aureus; Structure; Surface; System; Techniques; Technology; Testing; Therapeutic; Time; Training; bacterial community; base; biobank; blood glucose regulation; career; clinical predictors; cystic fibrosis patients; cystic fibrosis related diabetes; fecal microbiome; genetic predictors; genetic variant; glucose monitor; glycemic control; gut microbiome; improved; innovation; insight; instrument; lung microbiome; mathematical algorithm; metagenomic sequencing; microbial; microbiome; microbiome alteration; microbiome composition; microbiome research; mortality; novel; patient population; polygenic risk score; pulmonary function; response; trait; treatment as usual; treatment response; trial design

Cystic fibrosis related diabetes (CFRD) is the most common non-pulmonary complication of cystic fibrosis (CF), affecting up to 50% of adults. This diagnosis is linked to more pulmonary exacerbations, worsening lung function, and increased mortality compared to those without CFRD. Individuals with CFRD have more Pseudomonas Aeruginosa and Staphylococcus Aureus pulmonary infections determined by culture based microbial analysis. However, the specific microbiome seen in CFRD and how the microbiome changes with glycemic manipulation is not understood. The development of CFRD may also be influenced by genetic traits for insulin resistance and beta cell function, though studies evaluating this are limited. Insulin is the only recommended treatment that has been shown to improve pulmonary outcomes in CFRD; however, good glycemic control is difficult to achieve in this patient population due to high carbohydrate intake, frequent hypoglycemia, and the added burden of diabetes tasks. Artificial pancreas (AP) technology is a promising approach to controlling blood glucose with greater accuracy and ease than conventional methods. We have funding to study an AP device, the bionic pancreas (BP), in a randomized parallel design clinical trial in subjects with poorly controlled CFRD (R01DK119699-01, PI:Putman). These subjects will be randomized to usual care (UC) or the BP for 6 months, evaluating the impact of the BP not only on glycemic control but also on CF-specific outcomes including nutritional status and pulmonary function. We will leverage this funded trial to investigate novel clinical and genetic predictors of CFRD and will use state-of-the-art microbiome analytic techniques to understand how glycemic control impacts microbiome diversity in CF. Aim 1 will compare the microbiome in CFRD subjects participating in this trial to biorepository samples from non-CFRD subjects and determine how baseline glycemia influences the microbiome. Aim 2 will investigate genetic and clinical predictors of baseline glycemia and response to the BP intervention in subjects with CFRD. Aim 3 will evaluate how strict glycemic control achieved with the BP impacts microbiome diversity over 6 months, and if the change in lung function seen with improved glycemia is mediated through the change in microbiome. In summary, the research and mentoring plan proposed in this K23 application will test innovative hypotheses about glycemic traits and the microbiome in patients with CFRD, will broaden our understanding of CFRD, and will provide the necessary training and investigational niche for Dr. Brenner to develop a successful, independent career in clinical research.

囊性纤维化相关糖尿病（CFRD）是糖尿病最常见的非肺部并发症， 囊性纤维化（CF），影响高达50%的成年人。这种诊断与更多的肺部疾病有关。 急性加重、肺功能恶化和死亡率增加 混凝土面板堆石坝混凝土面板堆石坝个体有更多的假单胞菌和葡萄球菌 通过基于培养的微生物分析确定金黄色肺部感染。但 CFRD中观察到的特定微生物组以及微生物组如何随血糖变化而变化 操纵不被理解。混凝土面板堆石坝的发展也可能受到遗传因素的影响 胰岛素抵抗和β细胞功能的特征，尽管评估这一点的研究有限。 胰岛素是唯一被推荐的治疗方法，已被证明可以改善肺 CFRD的结局;然而，该患者难以实现良好的血糖控制 由于高碳水化合物摄入、频繁的低血糖和 糖尿病任务人工胰腺（AP）技术是一种很有前途的血液控制方法 与传统方法相比，更精确和更容易地测量葡萄糖。我们有资金来研究 在受试者中进行的随机平行设计临床试验中， 控制不良的混凝土面板堆石坝（R 01 DK 119699 -01，PI：Putman）。这些受试者将接受随机化 常规治疗（UC）或BP 6个月，评估BP不仅对血糖的影响， 控制，但也对CF的具体结果，包括营养状况和肺功能。 我们将利用这项资助的试验来调查新的临床和遗传预测CFRD 并将使用最先进的微生物组分析技术来了解血糖控制 影响CF中的微生物组多样性。目标1将比较CFRD受试者的微生物组 参与本试验的非混凝土面板堆石坝受试者的生物储存样品，并确定如何 基线干扰影响微生物组。目标2将研究遗传和临床 预测基线血压和对CFRD受试者BP干预的反应。目的 3将评估BP实现的严格血糖控制如何影响微生物组多样性 6个月以上，如果肺功能的变化与肺功能改善有关， 通过微生物组的变化。 总之，本K23申请中提出的研究和指导计划将测试 关于CFRD患者血糖特征和微生物组的创新假设，将 拓宽我们对面板堆石坝的理解，并将提供必要的培训和调查 Brenner博士在临床研究中发展成功，独立的职业生涯。