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，研究了双膦酸盐治疗对脆性骨折女性骨组织特性的影响。她的长期目标是发展一个独立的研究事业，作为一个翻译骨科材料科学家专注于以骨质量受损和骨折风险增加为特征的疾病。拟议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的研究方向，使候选人能够在胶原蛋白和骨质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不同，候选人最近被聘为不同部门的助理教授。导师及顾问委员会：主要导师是伦斯勒理工学院（RPI）的Deepak Vashishth博士，他是表征先进技术贡献的国际领导者。 糖基化终产物（AGEs）对骨组织力学行为的影响。咨询委员会由Christopher埃尔南德斯博士组成，他将为骨骼微损伤的量化提供建议;大卫普特南博士将为职业发展提供建议;约瑟夫莱恩博士将为骨科和代谢性骨病提供建议;理查德博克曼博士将为内分泌学提供建议。工作环境：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，这是一个拥有31，250平方英尺开放实验室空间和27，250平方英尺核心实验室空间的综合体，包括CNC铣削，机械测试，超高效液相色谱（UPLC）设备以及生物化学，生物成像，细胞和分子生物学，显微镜，和蛋白质组学培训计划：培训计划包括在Mentor实验室进行的研究培训，包括使用荧光和UPLC分析胶原蛋白生物化学的技术，以及使用机械测试和microCT定量骨组织中的微损伤。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，骨杂志俱乐部，代谢性骨病和内分泌学大圆桌会议/杂志俱乐部;每年至少2次全国会议的演讲。调研：2型糖尿病（T2 DM）患者尽管骨密度正常或高于非糖尿病患者，但骨折风险反而增加，这表明葡萄糖代谢受损会降低骨质量。通过与高血糖相关的胶原蛋白的非酶糖化形成AGEs已被提出为糖尿病骨中骨质量受损的机制，但AGEs对T2 DM患者骨组织中骨机械性能的影响尚未研究。本申请的目的是研究T2 DM患者骨组织中胶原交联、微损伤形态和结构特性相对于对照患者的变化。中心假设是，与T2 DM相关的骨组织非酶糖化增加通过降低组织韧性和将微损伤模式从弥漫性损伤转变为裂纹样形态（相对于非糖尿病组织）而导致骨脆性。因此，目的1是通过血清血红蛋白HbA 1c（HbA 1c）、骨组织非酶糖化以及2型糖尿病患者和非糖尿病患者皮质骨和松质骨的结构特性评估血糖控制。使用2型糖尿病和非糖尿病患者的松质骨和皮质组织，将关联以下特性：HbA 1c、通过荧光测量评估的总AGE、通过FTIR光谱评估的组成特性和通过机械测试评估的结构特性。目的2是表征与非糖尿病患者相比，T2 DM患者的皮质骨和松质骨组织中非酶糖化的局部变化对微损伤形态的影响。使用来自T2 DM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AGEs将与微损伤形态学相关。拟议的研究预计将确定T2 DM患者的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独立性的手段，作为一名具有胶原蛋白生物化学新专业知识的翻译骨科材料科学家。对候选人的机构承诺：候选人在康奈尔大学拥有终身教职，该大学为研究生提供了新装修的实验室，启动包和支持。