ENPP1 regulation of mammalian bone mass

ENPP1 对哺乳动物骨量的调节

• 批准号: 10353666
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 43.67万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10353666
• 关键词: Adolescent; Adult; Aging; Animal Model; Architecture; Automobile Driving; Biochemical; Biological; 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; base; bench to bedside; bone; bone fragility; bone loss; bone mass; calcification; 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; skeletal tissue; soft tissue; success; translational study

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.

失活 包括 韧带 早发性 人类ENPP1基因突变导致异常软组织和骨骼矿化障碍， 常染色体隐性遗传性低磷性软骨病(ARHR2) (OPLL)和纯合子缺乏症的婴儿泛发性动脉钙化(GACI)，以及 骨质疏松症(EOOP) ， ENPP1单倍体功能不全。因此，ENPP1缺乏的患者表现为 矛盾的矿化，同时伴有低骨量和肾脏、肌腱、 和血管系统。在老年患者的普通医学人群中也存在矛盾的矿化， 慢性肾脏病矿物质骨病(CKD-MBD)患者。骨折风险和高风险 CKD-MBD患者的死亡率在过去20年中没有变化，尽管在其他方面取得了显著进展 骨骼疾病，说明对CKD-MBD的理解和治疗仍然存在严重限制。 ENPP1缺乏及其内在矛盾成矿作用的研究将有助于识别和验证 ENPP1调节骨量的信号通路；我们坚信这一途径将使 长期存在的问题阻碍了我们对矛盾矿化的理解，使更好的治疗成为可能 这些病人的代理人。 ENPP1是人类唯一能产生PPI的酶，PPI是一种强烈的抑制骨矿物质积累的酶。 现存的骨基质。因此，人们可以预料到，导致低PPI的疾病将导致 骨量和骨量，而不是在人类和小鼠身上观察到的低骨量。因此，该机制 根据对ENPP1酶的催化作用的理解，ENPP1是如何导致骨量减少的并不明显 单打独斗。作为对这一悖论的回应，我们假设存在催化独立的ENPP1 调节哺乳动物骨量的信号通路。这项建议旨在(A)建立 参与，(B)定义催化依赖和独立的遗传和蛋白质信号转导 ENPP1调节骨量的途径，以及(C)量化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记物。要完成 为了达到这些目的，我们将使用新的动物模型，将ENPP1蛋白信号从ENPP1催化中分离出来 和我们设计和设计的新型和专有生物制品来激活ENPP1催化和 体内非催化信号转导。调查小组有很强的成功历史，证明了这一点 最近的几个出版物支持总体假设、具体目标和床边的替补 已进入临床的治疗GACI和ARHR2的新型生物制剂的开发，从而验证了 这一提议的科学严谨性、实验方法和科学影响。