The Molecular Pathology and Etiology of Nephrogenic Systemic Fibrosis

肾源性系统性纤维化(NSF)是一种与Gd(Gd3+)相关的破坏性疾病 严重终末期或慢性肾脏疾病(ESRD或CKD)患者的造影剂(GBCA)。一场严重的 多器官疾病，包括肺、心脏、横隔膜、骨骼、皮肤和骨骼肌，是其特征。 这种疾病的危害。GBCA是磁共振成像(MRI)的重要造影剂，是一种强大的医学 提供不同软组织(如脑、肌肉、心脏、肿瘤、血管)的3D内部成像的工具 以及发炎的区域。从造影剂中释放出的游离Gd3+被认为在 NSF的病理生理，因为游离Gd3+是有毒的。Gd3+从GBCA中释放的主要原因和原因 在NSF的情况仍不清楚。 我们有强有力的证据表明，一种小的(2.2 kDa)，酸性，高活性，磷酸化和蛋白水解酶 抵抗性骨基质多肽(ASARM多肽)起主要作用。ASARM-多肽是一种有效的抑制剂 与钙离子和羟基磷灰石结合强烈的矿化。值得注意的是，Gd3+的离子半径(107.8 Pm)为 接近于Ca~(2+)(114 PM)，干扰Ca~(2+)激活或介导的生化和 生理过程。ASARM多肽增加是骨矿化异常和骨矿化异常的原因 家族性低磷血症性软骨病和肿瘤引起的肾脏磷酸盐转运缺陷 骨软化症。ASARM-肽被蛋白质分解释放到骨骼中，并从一个骨骼家族中循环- 具有ASARM基序的基质蛋白(兄弟姐妹)。这些蛋白质都映射到一个单一的簇 在小鼠的4号染色体和人类的5号染色体上。它们包括DMP1、MEPE、骨桥蛋白、牙本质唾液酸 磷酸蛋白(DSPP)、骨涎蛋白、他汀类和釉质蛋白。 我们假设肾功能受损的肾性骨营养不良患者的一个子集，异常 ASARM多肽水平和GBCA的肾脏清除率降低是NSF的高风险因素，因为：(A)增加 ASARM多肽与GBCA的结合及(B)ASARM诱导Gd3+-GBCA复合体失稳 导致有毒Gd3+的局部释放。 我们的目标是：(1)。体内外ASARM多肽是否与GBCA特异性结合 特别是与NSF相关的那些；(2)确定ASARM多肽在体内和体外是否诱导 从GBCA络合物中释放游离Gd3+；(3)确定一个生物工程4.2 kDa多肽(SPR4) 通过竞争性结合ASARM-肽来稳定Gd3+-GBCA复合体；(4)使用NSF大鼠模型 显示SPR4多肽是否是预防疾病或降低风险的佐剂 GBCA增强MRI扫描：(5)确定ASARM多肽和Gd3+复合体是否在 人类NSF样本并与疾病有关。

Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+) based contrast-agents (GBCAs) in patients with severe end stage or chronic kidney disease (ESRD or CKD). A severe multiple organ condition, that includes lungs, heart, diaphragm, bone, skin and skeletal muscles, is characteristic of the disease. GBCAs are important contrast agents for magnetic resonance imaging (MRI) - a powerful medical tool that provides 3D internal imaging of different soft tissues such as brain, muscle, heart, tumors, blood vessels and areas of inflammation. Release of free Gd3+ from the contrast-agent is thought to play a major role in the pathophysiology of NSF since free Gd3+ is toxic. The primary cause and etiology of Gd3+ release from GBCAs in NSF remains unknown. We have strong evidence that a small (2.2 kDa), acidic, highly-reactive, phosphorylated and protease resistant bone-matrix peptide (ASARM-peptide) plays a major role. ASARM-peptides are potent inhibitors of mineralization that bind strongly to Ca2+ and hydroxyapaptite. Of note, the ionic radius of Gd3+ (107.8 pm) is close to that of Ca2+ (114 pm) and this element interferes with Ca2+ activated or mediated biochemical and physiological processes. Increased ASARM-peptides are responsible for bone-mineralization abnormalities and contribute to renal phosphate-handling defects in familial hypophosphatemic rickets and tumor induced osteomalacia. The ASARM-peptide is proteolytically released into bone and circulation from a family of bone- matrix proteins (SIBLINGs) that characteristically have ASARM-motifs. These proteins all map to a single cluster on chromosome 4 in mice and 5 in humans. They include DMP1, MEPE, osteopontin, dentin sialo phosphoprotein (DSPP), bone-sialoprotein, statherin and enamelin. We hypothesize that a subset of renal-compromised patients with renal osteodystrophy, abnormal ASARM-peptide levels and reduced renal clearance of GBCAs are at high risk for NSF because of: (A) Increased binding of ASARM-peptide to GBCA and (B) ASARM-induced destabilization of the Gd3+-GBCA complex resulting in localized release of toxic Gd3+. Our aims are to: (1). Determine whether ASARM-peptide in vitro and in vivo specifically binds to GBCAs particularly those associated with NSF; (2) Determine whether ASARM-peptide in vivo and in vitro induces release of free Gd3+ from the GBCA complex; (3) Determine whether a bio-engineered 4.2 kDa peptide (SPR4) stabilizes the Gd3+-GBCA complex by competitively binding to ASARM-peptide; (4) Use a rat model of NSF to show whether SPR4-peptide is an adjuvant for preventing the disease or reducing risk in patients requiring GBCA enhanced MRI scans: (5) Determine whether ASARM peptides and Gd3+ complexes are increased in human NSF samples and associated with disease.