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(PQ12) Targeting SMPDL3b to Prevent Radiation-Induced Nephrotoxicity

(PQ12) 靶向 SMPDL3b 预防辐射引起的肾毒性

基本信息

批准号：
10442691
负责人：
BRIAN MARPLES
金额：
$ 37.41万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442691
关键词：
ANGPT1 gene Acids Actin-Binding Protein Actins Acute Affect Agonist Apoptosis Atrophic Bilateral Binding Biological Markers Blood Blood Vessels C57BL/6 Mouse Cancer Patient Cell Culture Techniques Cell Survival Cell membrane Cells Ceramides Chronic Cisplatin Clinical Clinical Treatment Coculture Techniques Combined Modality Therapy Complication Creatinine Cytosol Data Development Dose Doxycycline EDN1 gene Endothelial Cells Endothelin-1 Endothelium Engineering Enzymes Fibrosis Fractionated radiotherapy Functional disorder Goals Homeostasis Human Impaired Renal Function In Vitro Inflammation Injury Injury to Kidney Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Knowledge Link Lipids MS4A1 gene Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Mediator of activation protein Modality Molecular Molecular Target Monoclonal Antibodies Morbidity - disease rate Morphology Mus Organ Oxidative Stress Pathway interactions Placebo Control Play Proteinuria Quality of life Radiation Radiation Injuries Radiation Tolerance Radiation induced damage Radiation therapy Radio Regulation Renal function Retreatment Role Serum Severities Signal Transduction Solid Sphingolipids Sphingomyelinase Sphingosine Testing Time Tissues Tubular formation Urine Vascular Endothelial Growth Factors Western Blotting base cancer radiation therapy cell injury cellular targeting chemokine chemotherapy clinical development clinically relevant cytokine ezrin glomerular endothelium image guided improved in vivo irradiation kidney cortex kidney dysfunction kidney vascular structure mouse model nephrotoxicity novel overexpression paracrine podocyte prevent protein expression radiation mitigation radiation mitigator receptor rituximab sphingosine 1-phosphate standard of care targeted agent

项目摘要

PROJECT SUMMARY Radiation nephropathy (RN) is less common than chemotherapy-induced nephrotoxicity but still represents a serious late complication after radiation therapies for cancer. RN is irreversible and no effective clinical treatments exist to prevent RN or ameliorate radiation-associated kidney injury. Podocyte loss, tubular atrophy and endothelial damage have been linked with RN, but the molecular mechanisms governing RN are not known. We discovered that the enzyme sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL3b) is an important regulator of radiation damage in renal podocytes after single dose (SD) radiotherapy (RT). Radiation damage reduced SMPDL3b expression triggering the cellular relocation of ezrin and a morphological change that altered podocyte functionality. Treatment with rituximab, which we demonstrated to bind SMPDL3b and to protect podocyte morphology, reduced SD RT induced RN in C57BL/6 mice but not in our newly-developed conditional podocyte-specific SMPDL3b knock-out mice. Based on these data we hypothesize that sphingolipids play a vital role in radiation-induced podocytopathy which governs RN. The objective is to investigate the mechanistic role of SMPDL3b in renal injury after fractionated low-dose radiotherapy (F-RT) with concurrent cisplatin (CDDP) as this represents a standard of care for many solid cancers. Our long-term goal is to discover a molecular-based protective or mitigating strategy for RN, and potentially chemotherapy-induced nephrotoxicity. We will test our hypothesis with the following three specific aims using a combined in vivo-in vitro approach: Aim 1: To determine if SMPDL3b regulates severity and latency of RT-associated kidney injury and functional RN after clinically-relevant F-RT, CDDP and concurrent F-RT+CDDP. This aim will also explore the role of SMPDL3b in tissue tolerance for RT retreatment injury, using C57BL/6 mice and our unique SMPDL3b-knockout and SMPDL3b-inducible mouse models. Aim 2: To determine the mechanism by which podocyte expression of SMPDL3b affects RT-mediated podocyte and glomerular endothelial cell (GEC) injury. We hypothesize that SMPDL3b affects RT induced compartmentalization of podocyte ezrin and affects GECs via altered endothelin-1 (EDN1) and END1 receptor type A (EDNRA) cross talk. GEC survival after RT will be studied by co-culturing GECs with podocytes lacking or expressing SMPDL3b. Aim 3: To determine if targeting sphingolipids prevents RN. We will investigate if protection of SMPDL3b or S1P will avert long-term functional renal injury in C57BL/6 mice after F-RT, CDDP and F-RT+CDDP. Mechanisms will be confirmed using our unique SMPDL3b-knockout and SMPDL3b-inducible mouse models. The findings from these studies will be significant because they offer the potential for molecular-targeted mitigation for RN, and radiation-associated kidney injury, after RT and combined modality injury.

项目概要放射性肾病 (RN) 不如化疗引起的肾毒性常见，但仍代表着一种癌症放射治疗后严重的晚期并发症。 RN是不可逆的，临床上尚无有效的存在预防 RN 或改善放射相关肾损伤的治疗方法。足细胞丢失、肾小管萎缩和内皮损伤与 RN 有关，但控制 RN 的分子机制尚不清楚。我们发现鞘磷脂磷酸二酯酶酸样 3b (SMPDL3b) 是一种重要的酶单剂量（SD）放射治疗（RT）后肾足细胞辐射损伤的调节剂。辐射损伤 SMPDL3b 表达的减少触发了 ezrin 的细胞重新定位以及改变的形态学变化足细胞功能。使用利妥昔单抗治疗，我们证明它可以结合 SMPDL3b 并保护足细胞形态，C57BL/6 小鼠中 SD RT 诱导的 RN 减少，但在我们新开发的条件条件下则没有足细胞特异性 SMPDL3b 敲除小鼠。根据这些数据，我们假设鞘脂起着至关重要的作用在控制 RN 的辐射诱导足细胞病中的作用。目的是研究 SMPDL3b 在分次低剂量肾损伤中的机制作用放疗 (F-RT) 联合顺铂 (CDDP)，因为这代表了许多实体瘤的护理标准癌症。我们的长期目标是发现一种基于分子的 RN 保护或缓解策略，并且潜在的化疗引起的肾毒性。我们将用以下三个具体内容来检验我们的假设使用体内和体外相结合的方法旨在：目标 1：确定 SMPDL3b 是否调节 RT 相关肾损伤和功能性肾损伤的严重程度和潜伏期临床相关 F-RT、CDDP 和并发 F-RT+CDDP 后进行 RN。这一目标还将探讨使用 C57BL/6 小鼠和我们独特的 SMPDL3b 敲除技术，SMPDL3b 对 RT 再治疗损伤的组织耐受性和 SMPDL3b 诱导小鼠模型。目标 2：确定 SMPDL3b 足细胞表达影响 RT 介导的足细胞的机制和肾小球内皮细胞（GEC）损伤。我们假设 SMPDL3b 影响 RT 诱导的足细胞埃兹蛋白的区室化并通过改变内皮素-1 (EDN1) 和 END1 受体影响 GEC A 型 (EDNRA) 串扰。 RT 后 GEC 的存活率将通过与缺乏足细胞的 GEC 共培养来研究或表达SMPDL3b。目标 3：确定靶向鞘脂是否可以预防 RN。我们将调查是否保护 SMPDL3b 或 S1P 将避免 F-RT、CDDP 和 F-RT+CDDP 后 C57BL/6 小鼠的长期功能性肾损伤。机制将使用我们独特的 SMPDL3b 敲除和 SMPDL3b 诱导小鼠模型进行确认。这些研究的结果将具有重要意义，因为它们提供了分子靶向治疗的潜力缓解 RT 和联合损伤后的 RN 和放射相关肾损伤。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detection and Quantification of Lipid Droplets in Differentiated Human Podocytes.

分化的人足细胞中脂滴的检测和定量。

DOI：
10.1007/978-1-4939-9488-5_17
发表时间：
2019
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Mallela,ShamroopKumar;Patel,DevangMaheshkumar;Ducasa,GloriaMichelle;Merscher,Sandra;Fornoni,Alessia;Al-Ali,Hassan
通讯作者：
Al-Ali,Hassan

Noninvasive assessment of radiation-induced renal injury in mice.

DOI：
10.1080/09553002.2021.1876950
发表时间：
2021
期刊：
International journal of radiation biology
影响因子：
2.6
作者：
Ahmad A;Shi J;Ansari S;Afaghani J;Molina J;Pollack A;Merscher S;Zeidan YH;Fornoni A;Marples B
通讯作者：
Marples B

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS.

DOI：
10.33696/signaling.1.013
发表时间：
2020-09-01
期刊：
Journal of cellular signaling
影响因子：
0
作者：
Mitrofanova, Alla;Drexler, Yelena;Fornoni, Alessia
通讯作者：
Fornoni, Alessia

Sphingomyelin phosphodiesterase acid like 3B (SMPDL3b) regulates Perilipin5 (PLIN5) expression and mediates lipid droplet formation.

DOI：
10.1016/j.gendis.2021.12.014
发表时间：
2022-11
期刊：
Genes & diseases
影响因子：
6.8
作者：
Mallela SK;Ge M;Molina J;Santos JV;Kim JJ;Mitrofanova A;Al-Ali H;Marples B;Merscher S;Fornoni A
通讯作者：
Fornoni A

ABCA1 deficiency contributes to podocyte pyroptosis priming via the APE1/IRF1 axis in diabetic kidney disease.