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.

灭活包括韧带早期发作人ENPP1的突变导致异常软组织和骨骼矿化障碍，常染色体隐性下磷酸ri鼠（ARHR2）的后纵向骨化（OPLL）和纯合缺陷中婴儿期（GACI）的广义动脉钙化和骨质疏松症（EOOP），，，， ENPP1单倍宽度。因此，ENPP1缺陷患者表现出矛盾的矿化，肾脏，肌腱，骨质降低和进行性钙化同时进行和脉管系统。老龄化患者的一般医学人群中也存在矛盾的矿化化，以及患有慢性肾脏疾病矿物质和骨骼疾病（CKD-MBD）的患者。破裂风险和高尽管在其他方面取得了重大进展，但在过去20年中，CKD-MBD患者的死亡率没有改变骨骼疾病，说明了对CKD-MBD的理解和治疗的持续严重局限性。 ENPP1缺乏症及其固有的矛盾矿化的研究将有助于识别和验证 ENPP1调节骨骼的信号通路；我们坚信这种方法会告知长期存在的问题阻碍了我们对矛盾矿化的理解，从而使更好的治疗能力这些患者的代理。 ENPP1是唯一产生PPI的酶，PPI是一种强的骨矿物质抑制剂现存的骨基质。因此，人们会预计，诱导低PPI的疾病会导致增加骨骼质量和体积，而不是在人类和小鼠中观察到的低骨质量。因此，机制基于对酶催化的理解，ENPP1诱导低骨质量并不明显仅活动。为了响应这种悖论，我们假设存在催化独立的ENPP1 信号通路调节哺乳动物骨骼。该提议试图（a）建立途径涉及，（b）定义催化依赖和独立遗传和蛋白质信号转导 ENPP1调节骨骼的途径，（c）定量其对骨骼脆弱性的影响，微结构，生长以及与骨矿化相关的生物标志物。完成这些目的，我们将使用新型动物模型，这些模型将ENPP1蛋白质信号从ENPP催化中取消以及我们设计和设计的新颖和专有生物制剂，以激活ENPP催化和体内催化非依赖性信号传导。调查团队拥有成功的历史，这证明了最近的一些出版物支持总体假设，具体目的和卧床的板凳开发已经进入诊所的新型生物制剂治疗GACI和ARHR2，从而验证了该提案的科学严谨，实验方法和科学影响。