权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

(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：
10163078
负责人：
BRIAN MARPLES
金额：
$ 44.01万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163078
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.

项目总结