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: 9017949
• 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/9017949
• 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; Health; 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; Osteoporotic; Outcome; Pathogenesis; Patient risk; Patients; Pattern; Performance; Population; Positioning Attribute; Prevention; Preventive treatment; Property; Proteins; Proteomics; Public Health; 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; crystallinity; diabetic; diabetic patient; glucose metabolism; glycation; glycemic control; graduate student; insight; mechanical behavior; member; non-diabetic; patient population; professor; programs; responsible research conduct; screening; skeletal; symposium; tenure track

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学博士学位，并完成了NIH F32奖学金，检查了双膦酸盐治疗对骨质疏松妇女的骨骼组织特性的影响，具有脆弱性骨折。她的长期目标是发展独立的研究职业，作为一种转化骨科材料，专注于以骨质损害和增加骨折风险为特征的疾病。拟议工作的直接目的是在胶原蛋白生物化学和骨微损伤方面提供重要的训练，以表征非酶糖基化在2型糖尿病患者中骨骼脆弱性中的作用。第二个目标是产生一个令人兴奋的新研究方向，以使候选人能够建立一个独立的胶原蛋白和骨质质量的利基市场，这与她在康奈尔大学的前博士学位导师的不同，该候选人最近被聘为另一个部门的助理教授。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。 胶原蛋白的糖基化终产物（年龄）至骨组织机械行为。咨询委员会由克里斯托弗·埃尔南德斯（Christopher Hernandez）博士组成，后者将建议量化骨骼微观损害。大卫·普特南（David Putnam）博士，他将为职业发展提供建议；约瑟夫·莱恩（Joseph Lane）医学博士，将为骨科和代谢骨病提供建议。理查德·鲍克曼（Richard Bockman）医学博士，他将就内分泌学提供建议。环境：康奈尔（Cornell）的研究/培训环境包括1500 ft2的专用实验室空间；多个共享的实验设施，包括微型计算机断层扫描（Microct）和傅立叶变换红外（FTIR）光谱；许多研讨会和期刊俱乐部；和初级教师的职业发展课程。 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,和蛋白质组学。培训计划：培训计划包括使用荧光和UPLC分析的胶原蛋白生物化学分析的导师实验室的研究培训，并使用机械测试和MicroCT对骨组织中微损伤进行定量。此外，培训计划还包括衰老分子生物学，科学家领导/管理技术的教学培训，多个资助机构的授予写作以及负责任的研究；参加生物医学工程研讨会，骨骼期刊俱乐部，代谢骨病和内分泌学大弹/期刊俱乐部；每年至少有2个国家会议的演讲。研究：尽管骨矿物质密度正常或相对于非糖尿病，但矛盾的是2型糖尿病（T2DM）的人矛盾的风险增加，这表明葡萄糖代谢受损会降低骨骼质量。通过与高血糖相关的胶原蛋白的非酶糖化形成，已提出是糖尿病骨骨质质量受损的机制，但是AGES对T2DM患者骨组织的AGE对骨骼机械性能的影响尚未研究。该应用的目的是将胶原蛋白交联，微塑料形态和结构特性的变化相关，而T2DM患者的骨组织中发生的结构特性则相对于对照患者而发生。中心假设是，与T2DM相关的骨组织非酶腺糖化的增加，可以通过减少组织韧性并将微塑料模式从弥漫性损伤转移到裂纹样形态上，从而导致骨骼脆弱性，相对于非糖尿病组织。因此，目标1是要关联2型糖尿病患者和非糖尿病患者的皮质和取消骨的血清血红蛋白HBA1C（HBA1C），骨组织非酶糖化和结构特性评估的血糖控制。使用2型糖尿病患者和非糖尿病患者的取消和皮质组织，以下特性将相关：HBA1C，通过荧光测量评估的总年龄，通过FTIR光谱法评估的组成特性以及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，T2DM患者皮质和取消骨组织中局部变异对非酶糖糖的影响。使用T2DM和非糖尿病对照患者的取消和皮质组织，在受损的骨骼中进行局部评估的年龄将与微观形态相关。预计拟议的研究将确定T2DM患者胶原蛋白特性和微型造影型模式的变化，并对糖尿病性骨折的发病机理产生重要的新见解，而同时，它们提供了建立候选人独立性作为翻译矫形器材料科学家的手段，具有胶原蛋白生物学的新专业知识。机构对候选人的承诺：候选人在康奈尔（Cornell）担任终身教师职位，该职位为新近翻新的实验室，初创企业包和研究生提供了支持。