Improving bone mass and quality in comorbid diabetes and chronic kidney disease

改善糖尿病和慢性肾病共病患者的骨量和骨质量

• 批准号: 10590035
• 负责人: Joseph Michael Wallace
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590035
• 关键词: Address; Adenine; Age; Age of Onset; Animal Disease Models; Animal Model; Biochemical; Biochemical Markers; Biochemistry; Biology; Bone Diseases; Bone Tissue; Cells; Chronic; Chronic Kidney Failure; Clinical; Collagen; Combined Modality Therapy; Complex; Coupled; Data; Defect; Diabetes Mellitus; Disease; Disease model; Estrogens; Exclusion; Exhibits; FDA approved; Fracture; General Population; Glucose tolerance test; Glycosylated hemoglobin A; Goals; Histology; Hydration status; Individual; Insulin; Intervention; Kidney; Late Effects; Measures; Mechanics; Minerals; Modeling; Molecular; Multiscale Mechanics; Mus; Musculoskeletal; Onset of illness; Osteogenesis; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Population; Prevalence; Property; Raloxifene; Raman Spectrum Analysis; Resistance; Resistance development; Risk; Severity of illness; Skeleton; Streptozocin; Structure of beta Cell of islet; Sum; Testing; Therapeutic; Tissues; Translating; Treatment Protocols; United States; Veterans; Work; aged; bone; bone mass; bone quality; comorbidity; comparison intervention; experimental study; fracture risk; glucose monitor; illness length; improved; in vivo; insulin tolerance; mechanical load; mechanical properties; military veteran; mortality; mortality risk; mouse model; nanoindentation; novel; physical property; prevent; sex; skeletal; skeletal disorder; structural imaging

PROJECT SUMMARY Diabetes and chronic kidney disease (CKD) consistently rank among the top ten chronic conditions in the United States in terms of prevalence and mortality. US veterans develop diabetes and CKD at an alarming rate, and comorbidity is twice as common in veterans compared with the general population. Both diseases put patients at increased risk of fracture and when fractures occur, patients are at a greater risk of death compared to other populations. Treatments for skeletal disease typically address deficits in either bone mass or tissue quality, which may be insufficient in cases of combined CKD and diabetes where there are known deficits in both. Despite their increasing comorbidity and well-established detrimental impacts on the skeleton, their skeletal interaction remains unexplored due to a lack of combined disease animal models and routine exclusion of patients with diabetes and/or CKD from clinical drug trials. The goal of this project is to study skeletal interactions between diabetes and CKD and to identify effective combination skeletal treatments. Using our novel combined model of diabetes and CKD, we will test the central hypothesis that increasing bone mass while concurrently improving tissue quality using combined therapies will increase bone mechanical strength, improve fracture resistance, and reverse adverse skeletal effects of late-stage diabetes+CKD. To achieve this goal, we will use our novel combined model of diabetes and CKD to investigate molecular, biochemical, and compositional changes coupled with multiscale structural and mechanical properties. Aim 1 will investigate the effects of combined disease as a function of age of onset and disease duration. Our lab has established a combined model of diabetes (streptozotocin) and CKD (adenine) that uniquely alters skeletal properties in young mice. 4 experiments will be used, inducing disease in either young or aged mice, and then allowing disease to progress for a short or longer duration. Key outcomes will include longitudinal insulin and glucose monitoring, HbA1c, insulin and glucose tolerance tests, pancreatic beta cell mass, and renal biochemistries. Skeletal outcomes will include biochemical markers of turnover and disease, structural imaging, bone formation/resorption histology, and a suite of multiscale mechanical and compositional properties. These experiments will clarify how diabetes and CKD impact the skeleton as a function of sex, age, and disease duration. In Aim 2, we will determine the skeletal impacts of treatment in late-stage disease utilizing mechanical loading (to improve bone mass) and Raloxifene (RAL – to improve tissue hydration and quality). We have shown that RAL, an FDA-approved agent for treating bone, specifically benefits bone material properties in a cell- and estrogen-independent manner. End points will be the same as those in Aim 1, including colocalized Raman spectroscopy and nanoindentation to characterize the mineral and collagen properties/mechanics of bone formed during the interventions compared with older bone. To increase translational value in Aim 3, we will determine the effects of pharmaceutical polytherapies initiated in late-stage combined diabetes and CKD. This work will challenge the idea that the effect of combined disease on the skeleton is equal to the sum of the parts and will have a positive impact in our at risk-veteran population by providing new ways to prevent or treat skeletal deficits associated with diabetes and CKD.

项目摘要 糖尿病和慢性肾脏病（CKD）一直是美国十大慢性疾病之一。 在流行率和死亡率方面。美国退伍军人以惊人的速度患上糖尿病和CKD， 退伍军人患科摩罗综合症的比例是普通人群的两倍。这两种疾病都使患者 骨折的风险增加，当骨折发生时，患者的死亡风险高于其他患者。 人口。骨骼疾病的治疗通常针对骨量或组织质量的缺陷， 在CKD和糖尿病合并的情况下可能不足，因为已知两者都有缺陷。尽管他们 增加的合并症和对骨骼的公认的有害影响，它们的骨骼相互作用 由于缺乏联合疾病动物模型和常规排除患有 糖尿病和/或CKD临床药物试验。这个项目的目标是研究骨骼之间的相互作用 糖尿病和CKD，并确定有效的组合骨骼治疗。使用我们的新组合模型， 糖尿病和CKD，我们将测试中心假设，增加骨量，同时改善 使用联合疗法的组织质量将增加骨机械强度，改善抗骨折性， 逆转晚期糖尿病+CKD对骨骼的不良影响。为了实现这一目标，我们将使用我们的小说 糖尿病和CKD的联合模型，用于研究分子、生化和成分变化 具有多尺度结构和机械特性。目的1将研究联合疾病作为一种 发病年龄和病程的函数。我们实验室建立了糖尿病联合模型 （链脲佐菌素）和CKD（腺嘌呤），独特地改变年轻小鼠的骨骼特性。4个实验将 使用，在年轻或年老的小鼠中诱导疾病，然后允许疾病进展较短或较长时间。 持续时间关键结果将包括纵向胰岛素和血糖监测、HbA 1c、胰岛素和血糖 耐受性测试、胰腺β细胞质量和肾脏生化。Skeleton的结果将包括生物化学 转换和疾病的标志物，结构成像，骨形成/吸收组织学，以及一套 多尺度机械和组成性质。这些实验将阐明糖尿病和CKD 对骨骼的影响与性别、年龄和病程有关。在目标2中，我们将确定骨骼 利用机械负荷（改善骨量）和雷洛昔芬治疗晚期疾病的影响 (RAL- 改善组织水合作用和质量）。我们已经证明，RAL，一种FDA批准的治疗 骨，特别是以细胞和雌激素非依赖性方式有益于骨材料性质。终点将 与目标1中的那些相同，包括共定位拉曼光谱和纳米压痕来表征 与老年人相比，在干预期间形成的骨的矿物质和胶原性质/力学 骨头为了增加目标3的转化价值，我们将确定药物综合疗法的效果 在晚期合并糖尿病和CKD中开始。这项工作将挑战这样一种观点， 骨骼上的疾病等于各部分的总和，并将对我们的风险退伍军人产生积极的影响。 通过提供新的方法来预防或治疗与糖尿病和CKD相关的骨骼缺陷。