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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)：应聘者拥有机械工程博士学位，并完成了NIH F32奖学金，以检验双膦酸盐治疗对患有骨质疏松性骨折的骨质疏松女性骨组织特性的影响。她的长期目标是发展独立的研究生涯，成为一名翻译整形外科材料科学家，专注于以骨骼质量受损和骨折风险增加为特征的疾病。这项拟议工作的直接目标是提供胶原蛋白生物化学和骨骼微损伤方面的关键培训，以便能够表征非酶糖化在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出一个独立的利基市场，这与她在康奈尔大学的前博士导师截然不同。在康奈尔大学，候选人最近被聘为另一个系的助理教授。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，他是描述先进技术贡献的国际领导者糖基化终产物(AGEs)中的胶原蛋白对骨组织的力学行为。咨询委员会成员包括克里斯托弗·埃尔南德斯博士，他将为骨骼微损伤的量化提供建议；大卫·普特南博士，他将为职业发展提供建议；约瑟夫·莱恩博士，他将为整形外科和代谢性骨疾病提供建议；理查德·博克曼博士，他将为内分泌学提供建议。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)和傅立叶变换红外光谱(FTIR)；许多研讨会和期刊俱乐部；以及初级教员的职业发展课程。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，包括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，包括数控铣削、机械测试、超高性能液相色谱(UPLC)设备和生物化学、生物成像、细胞与分子生物学、显微镜和蛋白质组学的核心设施。培训计划：培训计划包括在导师的实验室进行研究培训，使用荧光和UPLC分析胶原生物化学的技术，以及使用机械测试和MicroCT对骨组织的微损伤进行量化。此外，培训计划还包括在衰老的分子生物学、科学家的领导/管理技术、多个资助机构的拨款撰写和负责任的研究行为方面的教学培训；出席生物医学工程研讨会、骨杂志俱乐部和新陈代谢骨疾病和内分泌学大轮/杂志俱乐部；以及每年至少在两次全国会议上发表演讲。研究：矛盾的是，与非糖尿病患者相比，尽管骨密度正常或更高，2型糖尿病(T2 DM)患者的骨折风险仍会增加，这表明糖代谢受损会降低骨骼质量。糖尿病患者骨组织中AGEs的形成是糖尿病患者骨质量受损的一种机制，但在T2 DM患者的骨组织中，AGEs对骨力学性能的影响尚未得到研究。这项应用的目的是与对照患者相比，研究T2 DM患者骨组织中胶原交联、微损伤形态和结构特性的变化。中心假说是，与非糖尿病组织相比，与T2 DM相关的骨组织非酶糖基化增加，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隙状形态，从而导致骨脆性。因此，目标1是通过血清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皮质和松质骨的结构特性来评估血糖控制情况。使用来自2型糖尿病患者和非糖尿病患者的松质骨和皮质组织，以下属性将被关联：HbA1c，通过荧光测量评估的总年龄，通过FTIR光谱评估的组成属性，以及通过机械测试评估的结构属性。目的2与非糖尿病患者比较，研究非酶糖化局部变异对T2 DM患者皮质和松质骨组织微损伤形态的影响。使用来自T2 DM和非糖尿病对照组患者的松质骨和皮质组织，局部评估受损骨中的年龄将与微损伤形态相关。拟议的研究有望确定T2 DM患者胶原蛋白属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，它们为确立候选人作为具有胶原生物化学新专业知识的翻译整形外科材料科学家的独立性提供了手段。对候选人的机构承诺：候选人在康奈尔大学担任终身教职，康奈尔大学为研究生提供了新装修的实验室、创业方案和支持。