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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

基本信息

批准号：
9233019
负责人：
Eve Donnelly
金额：
$ 13.18万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
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/9233019
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 Hyperglycemia Impairment 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 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 bioimaging bisphosphonate bone bone fragility bone quality bone toughness career career development chemical bond cortical bone cost course development crosslink crystallinity diabetic diabetic patient fracture risk fragility fracture glucose metabolism glycation glycemic control graduate student insight mechanical behavior mechanical properties member non-diabetic patient population professor programs public health relevance responsible research conduct screening skeletal substantia spongiosa symposium tenure track

项目摘要

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，研究双膦酸盐治疗对骨质疏松性骨折女性骨组织特性的影响。她的长期目标是发展独立的研究事业，成为一名转化骨科材料科学家，专注于以骨质量受损和骨折风险增加为特征的疾病。这项工作的直接目标是提供胶原生物化学和骨微损伤的关键培训，以表征非酶糖基化在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质量方面开辟一个独立的利基，这与她在康奈尔大学的前博士导师不同，候选人最近被聘为康奈尔大学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，他是先进贡献的国际领导者