Low Molecular Weight Protein Nephrotoxicity

多发性骨髓瘤（MM）是一种恶性浆细胞疾病， 约占所有恶性肿瘤的1.1%，占血液恶性肿瘤的12-13%。 我们流行病学在我们的退伍军人群体中是相似的， 单克隆丙种球蛋白病的患病率，意义不明，一种癌前病变， 非裔美国退伍军人肾功能不全，通过血清肌酐升高≥ 1.3确定 mg/dl，通常（约48%）与MM相关，血清肌酐升高 浓度超过2.0mg/dl预示预后不良。一项大型研究得出结论， 肾功能的可逆性是一个更重要的预后因素比反应， 化疗最近的研究表明，单克隆免疫球蛋白游离轻链（FLC） 在多发性骨髓瘤中产生的是生物活性蛋白， 氧化应激在近端小管和促进上皮细胞生物学的显着变化。 本申请的工作假设是变量的物理化学结构 FLC的结构域决定了肾小管间质性肾病的类型和后果， 骨髓瘤 为了解决这一假设，提出了两个目标： 目标1。确定CDR 3结构域对蛋白水解的敏感性是否是管型的决定因素 肾病FLC可作为肾蛋白酶的底物; CDR 3的切割 结构域打开环结构，改变二级结构，从而影响与 THP。假设：CDR 3结构域对蛋白酶切割的抗性是决定性的。 与THP结合的决定因素和管型肾病的发展。 目标二。明确氧化还原信号在肾脏疾病进展中的作用 管型肾病假设：肾毒性单克隆FLC促进前- 炎症/纤维化状态，刺激阿基向CKD转变。 目的2.1确定信号转导子和转录激活子1（STAT 1）的功能 FLC肾毒性假设：肾脏上皮细胞中的STAT 1激活产生 IL-1b和TGF-β在阿基后CKD的发展中起关键作用 因为管型肾病 目的2.2确定是否涉及FLC产生过氧化氢的内在能力 在骨髓瘤肾的发展中。假设：氢气的产生 FLC的过氧化物是产生进行性肾损伤的关键因素。 该提案将使用体外和体内模型来确定单克隆FLC 产生促炎性和促纤维化生长因子，诱导肾小管间质性肾 纤维化该提案的长期目标是改变临床实践范式， 管理MM背景下发生的进行性肾衰竭，通过探索新的 制定限制慢性肾脏疾病发展的策略的理论概念 从而改善MM的预后。

Multiple myeloma (MM) is a malignant plasma cell disorder that has an incidence rate of about 1.1% among all malignancies and constitutes 12-13% of hematologic malignancies in the US. The epidemiology is similar in our veteran population and includes a 3-fold higher prevalence of monoclonal gammopathy of undetermined significance, a premalignant lesion, in African American veterans. Renal dysfunction, determined by serum creatinine elevation ≥ 1.3 mg/dl, is frequently (about 48%) associated with MM, and an increase in the serum creatinine concentration beyond 2.0 mg/dl portends a poor prognosis. One large study concluded that reversibility of renal function was a more important prognostic factor than response to chemotherapy. Recent work has shown that monoclonal immunoglobulin free light chains (FLC) produced in multiple myeloma are biologically active proteins that generate intracellular oxidative stress in the proximal tubule and promote significant changes in epithelial cell biology. The working hypothesis of this application is that the physicochemical structure of the variable domain of the FLC determines the type and consequences of tubulointerstitial renal disease in myeloma. To address this hypothesis, two aims are proposed: Aim 1. Determine if susceptibility of the CDR3 domain to proteolysis is a determinant of cast nephropathy. FLC may serve as substrates for kidney proteases; cleavage of the CDR3 domain opens the loop structure, changing the secondary structure, which affects binding to THP. Hypothesis: resistance of the CDR3 domain to protease cleavage is a critical determinant of binding to THP and development of cast nephropathy. Aim 2. Define the role of redox signaling in the development of progressive kidney disease in cast nephropathy. Hypothesis: nephrotoxic monoclonal FLCs promote a pro- inflammatory/fibrotic state that stimulates an AKI to CKD transition. Aim 2.1 Determine the function of Signal Transducer and Activator of Transcription 1 (STAT1) in FLC nephrotoxicity. Hypothesis: STAT1 activation in kidney epithelium produces IL-1b and TGF-b and plays a critical role in the development of CKD following AKI due to cast nephropathy. Aim 2.2 Determine if the intrinsic ability of the FLC to generate hydrogen peroxide is involved in the development of myeloma kidney. Hypothesis: the production of hydrogen peroxide by FLCs is a critical element in the generation of progressive kidney injury. The proposal will use in vitro and in vivo models to determine how monoclonal FLCs generate pro-inflammatory and pro-fibrotic growth factors that induce tubulointerstitial renal fibrosis. The long-term goal of this proposal is to shift clinical practice paradigms in the management of progressive renal failure occurring in the setting of MM, by exploring novel theoretical concepts to devise strategies that limit the development of chronic kidney disease and thereby improve outcomes in MM.