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ENPP1 regulation of mammalian bone mass

ENPP1 对哺乳动物骨量的调节

基本信息

批准号：
10630907
负责人：
DEMETRIOS BRADDOCK
金额：
$ 46.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630907
关键词：
Adolescent Adult Aging Animal Model Automobile Driving Biochemical Biological Biological Availability Biological Markers Biological Products Bone Diseases Bone Growth Bone Matrix Calcitriol Catalysis Cells Chronic Kidney Failure Clinic Data Development Diet Disease Engineering Enzymes Exhibits Experimental Designs Familial hypophosphatemic bone disease Fracture Genetic Genetic Transcription Genetic Transduction Goals Growth Human Inherited Investigation Kidney Ligaments Mammals Medical Minerals Molecular Morbidity - disease rate Mus Mutation Organ Osteoporosis Pathway interactions Patient Agents Patients Phenotype Physiologic Ossification Physiologic calcification Plasma Population Primary Cell Cultures Proteomics Public Health Publications Recording of previous events Regulation Regulatory Pathway Reporting Research Risk Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Skeleton Supplementation Survival Rate Tendon structure Therapeutic Therapeutic Agents Tissues Transgenic Mice United States National Institutes of Health arterial calcification of infancy autosome bench to bedside bone bone fragility bone loss bone mass calcification candidate identification conventional therapy design early onset enzyme replacement therapy experimental study fracture risk in vivo inhibitor inorganic phosphate mineralization mortality mouse model novel plasma cell membrane glycoprotein PC-1 posterior longitudinal ligament ossification response skeletal skeletal disorder soft tissue success translational study

项目摘要

Inactivating including Ligament early-onset mutations in human ENPP1 results in aberrant soft tissue and skeletal mineralization disorders, Autosomal Recessive Hypophosphatemic Rickets (ARHR2) Ossification of the Posterior Longitudinal (OPLL), and Generalized Arterial Calcification of Infancy (GACI) in homozygous deficiency, and osteoporosis (EOOP) in , ENPP1 haploinsufficiency. ENPP1 deficienct patients therefore exhibit paradoxical mineralization, with concurrent low bone mass and progressive calcifications in kidneys, tendons, and vasculature. Paradoxical mineralization is also present in the general medical population in aging patients, and in patients with chronic kidney disease mineral and bone disorder (CKD-MBD). Fracture risk and high mortality in CKD-MBD patients has not changed in the last 20 years despite significant progress in other skeletal disorders, illustrating continued serious limitations in the understanding and treatment of CKD-MBD. The study of ENPP1 deficiency and its inherent paradoxical mineralization, will serve to identify and validate signaling pathways by which ENPP1 regulates bone mass; we strongly believe that this approach will inform longstanding issues hampering our understanding of paradoxical mineralization, enabling better therapeutic agents for these patients. ENPP1 is the only human enzyme which generates PPi, a strong inhibitor of accrual of bone mineral in the extant bone matrix. One would anticipate, therefore, that disorders inducing low PPi would result in increased bone mass and volume, and not the low bone mass observed in humans and mice. Therefore, the mechanism by which ENPP1 induces low bone mass is not apparent based on an understand of the enzyme's catalytic activity alone. In response to this paradox, we hypothesize the presence of catalytically independent ENPP1 signaling pathways regulating mammalian bone mass. This proposal seeks to (a) establish the pathways involved, (b) define the catalytically dependent and independent genetic and protein signal transduction pathways by which ENPP1 regulates bone mass, and (c) quantitate their effect on bone fragility, microarchitecture, and growth, as well as on biomarkers associated with bone mineralization. To accomplish these Aims, we will use novel animal models which uncouple ENPP1 protein signaling from ENPP1 catalysis and novel and proprietary biologics we have designed and engineered to activate ENPP1 catalytic and catalytic-independent signaling in vivo. The investigative team has a strong history of success as evidenced by several recent publications supporting the overall hypothesis, the specific aims, and the bench to bedside development of a novel biologics treating GACI and ARHR2 that have entered the clinic, thus validating the scientific rigor, experimental approach, and scientific impact of this proposal.

灭活包括韧带早发性人ENPP 1的突变导致异常的软组织和骨骼矿化障碍，常染色体隐性低磷血症性佝偻病（ARHR 2）后纵骨骨化（OPLL）和纯合子缺陷的婴儿全身性动脉钙化（GACI），以及骨质疏松症（EOOP）， , ENPP 1单倍不足。因此，ENPP 1缺陷患者表现出反常的矿化，同时伴有低骨量和肾脏，肌腱，和脉管系统。局部矿化也存在于一般医学人群中的老年患者中，以及慢性肾病矿物质和骨紊乱（CKD-MBD）患者。骨折风险高 CKD-MBD患者的死亡率在过去20年中没有变化，尽管其他方面有显著进展，骨骼疾病，说明对CKD-MBD的理解和治疗仍然存在严重局限性。对ENPP 1缺乏及其内在矛盾矿化的研究，将有助于识别和验证 ENPP 1调节骨量的信号通路;我们坚信这种方法将告知长期存在的问题阻碍了我们对矛盾矿化的理解，这些患者的代理人。 ENPP 1是唯一产生PPi的人类酶，PPi是骨矿物质积累的强效抑制剂现存的骨基质。因此，人们可以预期，诱导低PPi的疾病将导致增加的骨量和体积，而不是在人类和小鼠中观察到的低骨量。因此，机制 ENPP 1诱导低骨量的机制并不明显，活动单独。为了回应这个矛盾，我们假设存在催化独立的ENPP 1，调节哺乳动物骨量的信号通路。该建议旨在：（a）建立涉及，（B）定义催化依赖性和独立的遗传和蛋白质信号转导 ENPP 1调节骨量的途径，和（c）定量它们对骨脆性的影响，微结构和生长，以及与骨矿化相关的生物标志物。完成这些目标，我们将使用新的动物模型，从ENPP 1催化解偶联ENPP 1蛋白信号以及我们设计和设计的新型专有生物制剂，用于激活ENPP 1催化和体内催化剂非依赖性信号传导。调查小组有着成功的悠久历史，最近的几篇出版物支持总体假设，具体目标，以及床旁的长凳开发了一种治疗GACI和ARHR 2的新型生物制剂，已进入临床，从而验证了科学的严谨性，实验方法，以及这一建议的科学影响。