Nonenzymatic glycation, bone quality, and microdamage in type 2 diabetic bone

2 型糖尿病骨的非酶糖化、骨质量和微损伤

• 批准号: 8487952
• 负责人: Eve Donnelly
• 金额: $ 13.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487952
• 关键词: Adult; Advanced Glycosylation End Products; Advisory Committees; Affect; Aging; Algorithms; Award; Biochemical; Biochemical Markers; Biochemistry; Biological Assay; Biology of Aging; Biomedical Engineering; Biotechnology; Bone Density; Bone Tissue; Cellular biology; Collagen; Complex; Core Facility; Diagnosis; Diagnostic; Diffuse Pattern; Direct Costs; Disease; Doctor of Philosophy; Elderly; Endocrinology; Engineering; Environment; Equipment; Faculty; Fellowship; Fluorescence; Fracture; Functional disorder; Funding Agency; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Grant; Hemoglobin; Histocompatibility Testing; Hyperglycemia; Individual; Institutes; Interdisciplinary Study; International; Journals; Laboratories; Leadership; Liquid Chromatography; Measurement; Measures; Mechanics; Mentors; Metabolic Bone Diseases; Microscopy; Minerals; Modeling; Molecular Biology; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Orthopedics; Outcome; Pathogenesis; Patients; Pattern; Performance; Population; Positioning Attribute; Prevention; Preventive; Property; Proteins; Proteomics; Public Health; Relative (related person); Research; Research Training; Risk; Role; Scientist; Serum; Spectroscopy, Fourier Transform Infrared; Techniques; Testing; Time; Tissues; Training; Treatment Protocols; United States National Institutes of Health; Variant; Woman; Work; World Health Organization; Writing; X-Ray Computed Tomography; base; bioimaging; bisphosphonate; bone; bone quality; bone toughness; career; career development; chemical bond; cost; crosslink; diabetic; diabetic patient; glucose metabolism; glycation; glycemic control; graduate student; insight; mechanical behavior; member; non-diabetic; patient population; professor; programs; public health relevance; responsible research conduct; screening; skeletal; symposium

DESCRIPTION (provided by applicant): The Candidate holds a PhD in mechanical engineering and completed an NIH F32 fellowship examining the effect bisphosphonate treatment on bone tissue properties in osteoporotic women with fragility fractures. Her long-term goal is to develop an independent research career as a translational orthopedic materials scientist focused on diseases characterized by compromised bone quality and increased fracture risk. The immediate goal of the proposed work is to provide critical training in collagen biochemistry and bone micro damage to enable characterization of the role of nonenzymatic glycation in bone fragility in patients with type 2 diabetes. A secondary goal is to generate an exciting new research direction to enable the Candidate to carve out an independent niche in collagen and bone quality that is distinct from that of her former PhD mentor at Cornell, where the Candidate has recently been hired as an assistant professor in a different department. Mentor and Advisory Committee: The primary Mentor is Dr. Deepak Vashishth of Rensselaer Polytechnic Institute (RPI), an international leader in characterizing the contribution of advanced glycation end products (AGEs) in collagen to bone tissue mechanical behavior. The Advisory Committee consists of Christopher Hernandez PhD, who will advise on quantification of micro damage in bone; David Putnam PhD, who will advise on career development; Joseph Lane MD, who will advise on orthopedics and metabolic bone disease; and Richard Bockman MD PhD, who will advise on endocrinology. Environment: The research/training environment at Cornell includes 1500 ft2 of dedicated lab space for the PI; multiple shared experimental facilities, including micro computed tomography (microCT) and Fourier transform infrared (FTIR) spectroscopy; numerous seminars and journal clubs; and career development courses for junior faculty members. At RPI Dr. Vashishth has 1400 ft2 of lab space in the Center for Biotechnology and Interdisciplinary studies, a complex with 31,250 ft2 of open lab space and 27,250 ft2 of core lab space, and includes equipment for CNC milling, mechanical testing, ultra performance liquid chromatography (UPLC), and core facilities for Biochemistry, Bioimaging, Cell & Molecular Biology, Microscopy, and Proteomics. Training Plan: The training plan includes research training in the Mentor's laboratory in techniques for analysis of collagen biochemistry using fluorescence and UPLC assays, as well as quantification of micro damage in bone tissue using mechanical testing and microCT. In addition, the training plan includes didactic training in the molecular biology of aging, leadership/management techniques for scientists, grant writing for multiple funding agencies, and responsible conduct of research; attendance at Biomedical Engineering seminars, Bone Journal Clubs, and Metabolic Bone Disease and Endocrinology Grand Rounds/Journal Clubs; and presentations at a minimum of 2 national conferences per year. Research: Individuals with type 2 diabetes mellitus (T2DM) paradoxically have increased fracture risk despite normal or greater bone mineral density relative to non-diabetics, suggesting that impaired glucose metabolism degrades bone quality. Formation of AGEs through nonenzymatic glycation of collagen associated with hyperglycemia has been proposed as a mechanism of impaired bone quality in diabetic bone, but the effect of AGEs on bone mechanical properties has not yet been investigated in bone tissue of patients with T2DM. The objective of this application is to relate alterations in collagen crosslinking, microdamage morphology, and structural properties that occur in the bone tissue of patients with T2DM relative to control patients. The central hypothesis is that increased bone tissue nonenzymatic glycation associated with T2DM contributes to bone fragility by reducing tissue toughness and shifting microdamage patterns from diffuse damage to crack-like morphologies, relative to non-diabetic tissue. Accordingly, Aim 1 is to relate glycemic control assessed by serum hemoglobin HbA1c (HbA1c), bone tissue nonenzymatic glycation, and structural properties in the cortical and cancellous bone of type 2 diabetic patients and non-diabetic patients. Using cancellous and cortical tissue from type 2 diabetic and non-diabetic patients, the following properties will be correlated: HbA1c, total AGEs assessed by fluorescence measurements, compositional properties assessed by FTIR spectroscopy, and structural properties assessed by mechanical testing. Aim 2 is to characterize the effect of local variations in nonenzymatic glycation on microdamage morphology in the cortical and cancellous bone tissue of T2DM patients compared to non-diabetic patients. Using cancellous and cortical tissue from T2DM and non-diabetic control patients, AGEs assessed locally in damaged bone will be correlated with microdamage morphology. The proposed studies are expected to identify changes in collagen properties and microdamage patterns in patients with T2DM and to yield important new insights into the pathogenesis of diabetic fractures, while, at the same time, they provide the means for establishing the Candidate's independence as a translational orthopedic materials scientist with new expertise in collagen biochemistry. Institutional Commitment to the Candidate: The Candidate holds a tenure-track faculty position at Cornell, which has provided a newly renovated laboratory, start-up package, and support for graduate students.

描述（由申请人提供）：候选人拥有机械工程博士学位，并完成了 NIH F32 奖学金，研究双磷酸盐治疗对患有脆性骨折的骨质疏松女性骨组织特性的影响。她的长期目标是作为一名转化骨科材料科学家发展独立的研究生涯，专注于以骨质量受损和骨折风险增加为特征的疾病。这项工作的直接目标是提供胶原蛋白生物化学和骨微损伤方面的关键培训，以表征非酶糖化在 2 型糖尿病患者骨脆性中的作用。第二个目标是产生一个令人兴奋的新研究方向，使候选人能够在胶原蛋白和骨骼质量方面开辟一个独立的利基市场，这与她在康奈尔大学的前博士导师的研究方向不同，候选人最近被聘为助理教授在不同的部门。导师和咨询委员会：主要导师是伦斯勒理工学院 (RPI) 的 Deepak Vashishth 博士，他是描述先进技术贡献的国际领导者。 胶原蛋白对骨组织的机械行为中的糖基化终末产物（AGE）。咨询委员会由 Christopher Hernandez 博士组成，他将就骨骼微损伤的量化提供建议； David Putnam 博士，将为职业发展提供建议； Joseph Lane 医学博士，将就骨科和代谢性骨病提供建议；理查德·博克曼医学博士，他将提供内分泌学方面的建议。环境：康奈尔大学的研究/培训环境包括 1500 平方英尺的 PI 专用实验室空间；多个共享实验设施，包括微型计算机断层扫描（microCT）和傅里叶变换红外（FTIR）光谱；众多研讨会和期刊俱乐部；以及初级教师的职业发展课程。在 RPI，Vashishth 博士在生物技术和跨学科研究中心拥有 1400 平方英尺的实验室空间，该综合体拥有 31,250 平方英尺的开放实验室空间和 27,250 平方英尺的核心实验室空间，包括 CNC 铣削、机械测试、超高性能液体设备色谱 (UPLC) 以及生物化学、生物成像、细胞和分子生物学、显微镜和蛋白质组学的核心设施。培训计划：培训计划包括在 Mentor 实验室进行研究培训，内容涉及使用荧光和 UPLC 测定分析胶原蛋白生物化学的技术，以及使用机械测试和 microCT 量化骨组织微损伤的技术。此外，培训计划还包括衰老分子生物学的教学培训、科学家的领导/管理技术、为多个资助机构撰写赠款以及负责任的研究行为；参加生物医学工程研讨会、骨期刊俱乐部以及代谢性骨病和内分泌学大查房/期刊俱乐部；每年至少在 2 次全国会议上发表演讲。研究：与非糖尿病患者相比，尽管骨矿物质密度正常或更高，2 型糖尿病 (T2DM) 患者的骨折风险却反而增加，这表明葡萄糖代谢受损会降低骨质量。与高血糖相关的胶原非酶糖化形成 AGE 已被认为是糖尿病骨中骨质量受损的机制，但 AGE 对骨机械性能的影响尚未在 T2DM 患者的骨组织中进行研究。本应用的目的是比较 T2DM 患者骨组织中发生的胶原交联、微损伤形态和结构特性相对于对照患者的变化。核心假设是，与非糖尿病组织相比，与 T2DM 相关的骨组织非酶糖化增加会降低组织韧性，并将微损伤模式从弥漫性损伤转变为裂纹状形态，从而导致骨脆性。因此，目标 1 是将通过血清血红蛋白 HbA1c (HbA1c)、骨组织非酶糖化以及 2 型糖尿病患者和非糖尿病患者的皮质骨和松质骨的结构特性评估的血糖控制联系起来。使用来自 2 型糖尿病和非糖尿病患者的松质和皮质组织，将关联以下特性：HbA1c、通过荧光测量评估的总 AGE、通过 FTIR 光谱评估的成分特性以及通过机械测试评估的结构特性。目标 2 是表征与非糖尿病患者相比，非酶糖化局部变化对 T2DM 患者皮质骨和松质骨组织微损伤形态的影响。使用 T2DM 和非糖尿病对照患者的松质和皮质组织，在受损骨中局部评估的 AGE 将与微损伤形态相关。拟议的研究预计将确定 T2DM 患者胶原蛋白特性和微损伤模式的变化，并对糖尿病骨折的发病机制产生重要的新见解，同时，它们提供了建立候选人作为转化性骨折的独立性的方法。骨科材料科学家，在胶原蛋白生物化学方面拥有新的专业知识。对候选人的机构承诺：候选人在康奈尔大学担任终身教授职位，该职位为研究生提供了新装修的实验室、启动方案和支持。