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.

项目概要 糖尿病和慢性肾病（CKD）一直位居美国十大慢性病之列 美国退伍军人糖尿病和慢性肾病的患病率和死亡率令人震惊。 与普通人群相比，退伍军人的合并症发病率是普通人群的两倍。 骨折的风险增加，并且当发生骨折时，与其他患者相比，患者的死亡风险更大 骨骼疾病的治疗通常针对骨量或组织质量的缺陷。 对于 CKD 和糖尿病合并的病例，尽管两者都存在已知的缺陷，但可能还不够。 日益增加的合并症和对骨骼及其骨骼相互作用的明确的痛苦影响 由于缺乏联合疾病动物模型以及常规排除患有这种疾病的患者，该问题仍有待探索。 临床药物试验中的糖尿病和/或 CKD 的目标是研究骨骼之间的相互作用。 糖尿病和慢性肾病，并使用我们的新型组合模型确定有效的骨骼联合治疗方法。 糖尿病和 CKD，我们将检验中心假设：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，提高抗骨折能力，并且 逆转晚期糖尿病+慢性肾病对骨骼的不利影响 为了实现这一目标，我们将使用我们的新型药物。 糖尿病和 CKD 的联合模型，用于研究分子、生化和成分变化 目标 1 将研究综合疾病的影响。 我们实验室建立了发病年龄和病程的联合模型。 （链脲佐菌素）和 CKD（腺嘌呤）独特地改变了年轻小鼠的骨骼特性，将进行 4 个实验。 使用，在年轻或年老的小鼠中诱导疾病，然后让疾病短期或长期发展 主要成果包括纵向胰岛素和血糖监测、HbA1c、胰岛素和血糖。 耐受性测试、胰腺β细胞质量和肾脏生化结果将包括生化结果。 周转和疾病标记物、结构成像、骨形成/吸收组织学以及一系列 这些实验将阐明糖尿病和 CKD 之间的关系。 作为性别、年龄和疾病持续时间的函数对骨骼的影响在目标 2 中，我们将确定骨骼。 利用机械负荷（以改善骨量）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 是 FDA 批准的治疗剂。 骨骼，以独立于细胞和雌激素的方式特别有利于骨骼材料特性。 与目标1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，干预期间形成的骨骼的矿物质和胶原蛋白特性/力学 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。 这项工作将挑战晚期合并糖尿病和 CKD 的效果的想法。 骨骼上的疾病等于各个部分的总和，将对我们处于危险中的退伍军人产生积极影响 通过提供新方法来预防或治疗与糖尿病和慢性肾病相关的骨骼缺陷。