Heparan Sulfate in Skeletal Development and Diseases

性状（由申请方提供）：硫酸乙酰肝素（HS）结合并功能性调节多种生长因子和形态发生素。遗传学研究表明，HS是模型动物中许多发育信号通路的组成部分。然而，我们对HS在哺乳动物骨骼发育和重塑中的作用的理解仍然相当有限，尽管事实上，最受HS异常表达影响的组织是骨。例如，编码HS合成所必需的酶的基因的突变引起遗传性多发性外生骨疣（HME），这是临床矫形外科中最常见的遗传性骨病症之一。在成人中，血栓栓塞和其他血管疾病患者的长期肝素治疗通常会导致类似骨质疏松症的低骨量状况。对HS在发育和成人骨骼系统中调节生长因子信号传导的机制的更好理解对于设计这些疾病的疗法至关重要。为了实现这一长期目标，我们采用了条件小鼠遗传学方法来剖析HS在骨骼发育和生理学中的功能。我们的证据表明，HS是必不可少的正常骨骼图案和骨骼细胞分化，参与关键的生长因子信号通路。基于这些和其他初步数据，我们提出了以下具体目标：1。分析软骨形成中HS功能的时间依赖性和结构特异性。2.确定软骨形成过程中HS调节BMP功能的机制。3.目的：探讨HS在骨形成和骨量调节中的作用。拟议的研究将对HME的发病机制产生新的见解，并可能有助于确定骨质疏松症的新药物靶点。公共卫生相关性：硫酸乙酰肝素对于正常的骨发育和生理学是必需的，如通过与硫酸乙酰肝素的异常表达直接相关的遗传性（遗传性多发性外生骨疣）和代谢性（肝素诱导的骨质疏松症）骨疾病的存在所说明的。本计画将利用先进的小鼠遗传学来阐明硫酸乙酰肝素调控骨细胞功能的分子机制。拟议的研究将产生新的见解遗传性多发性外生骨疣的发病机制，并可能有助于确定新的药物靶点骨质疏松症。

DESCRIPTION (provided by applicant): Heparan sulfate (HS) binds and functionally modulates a number of growth factors and morphogens. Genetic studies have revealed that HS is an integral component of many developmental signaling pathways in model animals. However, our understanding of the role of HS in the mammalian skeletal development and remodeling is still quite limited, and this is in spite of the fact that the tissue most affected by aberrant expression of HS is bone. For example, mutations of the gene encoding an enzyme essential for HS synthesis cause Hereditary Multiple Exostosis (HME), which is one of the most common genetic bone disorders in clinical orthopedics. In the adults, long-term heparin treatment for patients with thromboembolism and other vascular diseases often leads to a low bone mass condition resembling osteoporosis. The improved understanding of the mechanisms by which HS regulates growth factor signaling in the developing and adult skeletal system is critical for devising therapies for these diseases. Toward this long- term goal, we have employed conditional mouse genetics approaches to dissect the function of HS in skeletal development and physiology. Our evidence suggests that HS is essential for normal skeletal patterning and skeletal cell differentiation, being involved in key growth factor signaling pathways. Based on these and other preliminary data, we propose the following specific aims: 1. To dissect time-dependence and structural specificity of HS function in chondrogenesis. 2. To determine the mechanisms by which HS regulates BMP function during chondrogenesis. 3. To determine the role of HS in developmental bone formation and the regulation of bone mass. The proposed studies will generate new insights into the pathogenesis of HME, and may help define new drug targets for osteoporosis. PUBLIC HEALTH RELEVANCE: Heparan sulfate is essential for normal bone development and physiology, as illustrated by the existence of the genetic (hereditary multiple exostosis) and metabolic (heparin- induced osteoporosis) bone diseases that are directly linked to aberrant expression of heparan sulfate. This project will employ advanced mouse genetics to elucidate the molecular mechanisms by which heparan sulfate regulates bone cell function. The proposed studies will generate new insights into the pathogenesis of hereditary multiple exostosis, and may help define new drug targets for osteoporosis.