Biomolecular Markers for Safe Minimization of Immunosuppression

用于安全最小化免疫抑制的生物分子标记

基本信息

批准号：
10209348
负责人：
MANIKKAM SUTHANTHIRAN
金额：
$ 37.49万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-28 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10209348
关键词：
2019-nCoV Acute Renal Failure with Renal Papillary Necrosis Address Administrative Supplement Admission activity Allografting Bioinformatics Biological Assay Biopsy CD3E gene COVID-19 COVID-19 diagnosis COVID-19 outbreak COVID-19 patient CXCL10 gene Cells Clinical Cohort Studies Collection Complementary DNA Creatinine Custom Diagnosis Diagnostic Equation Functional disorder Funding Gene Expression Profiling Genes Goals Grant Health Personnel Hemorrhage Home Hospitalization Hour Immune Immune response Immunosuppression Kidney Transplantation Measurement Measures Messenger RNA Methods Molecular Monitor Outcome Patient Recruitments Patients Procedures RNA RNA Sequences Renal function Research Retrieval Ribosomal RNA Risk SARS-CoV-2 positive SARS-CoV-2 transmission Sampling Serum Specimen Symptoms Therapeutic immunosuppression Time Training Urine Validation base biobank cohort genetic signature innovation insight kidney allograft prognostic recruit response severe COVID-19 symptomatic COVID-19 symptomatology tool transcriptome transcriptome sequencing transcriptomics urinary

项目摘要

We seek additional funds for research responsive to the SARS-CoV-2/COVID-19 outbreak that is in scope of our ongoing grant R37AI051652 “Biomolecular Markers for Safe Minimization of Immuno-suppression.” From March 13, 2020 to April 20, 2020, we hospitalized 39 kidney allograft recipients positive for SARS-CoV-2 and with Covid-19 symptoms. Among these patients, 20 (51%) developed acute kidney injury (AKI). Importantly, graft dysfunction due to AKI recovered in 9 patients only and did not recover in 11 patients as of May 15, 2020. None underwent a diagnostic allograft biopsy because of biopsy-associated complications such as bleeding are potentially much more serious in this cohort and also to limit potential exposure of healthcare workers to SARS- CoV-2 during the invasive biopsy procedure. In the absence of a diagnostic biopsy, none received anti-rejection therapy. Whether the graft dysfunction was reversible or nonreversible could not be predicted at the time of graft dysfunction diagnosis. The dynamics of anti-allograft response from the reductions in their immunosuppressive therapy could not be captured with the available clinical analytes. To address these existing challenges, we propose the following: Specific Aim 1. To perform RNA sequencing of urinary cells and investigate whether the urinary cell transcriptome, ascertained at the time of graft dysfunction, is prognostic of allograft dysfunction. Urine will be collected at the time of graft dysfunction diagnosis and RNA isolated from urinary cells. RNA from 30 patients with reversible graft dysfunction; RNA from 30 patients with nonreversible graft dysfunction; and RNA from 30 patients with no graft dysfunction during the 3 months since Covid-19 diagnosis will be RNA sequenced and bioinformatics performed. The goal is to determine whether the urinary cell transcriptome profile, ascertained at the time of graft dysfunction, is prognostic of graft dysfunction and distinguishes those with reversible graft dysfunction from those with nonreversible graft dysfunction. Specific Aim 2. To measure urinary cell 3-gene signature score in sequential urine samples from Covid-19 kidney allograft recipients. Urine will be collected at baseline and sequentially every two weeks for 3 months since Covid-19 diagnosis. We will retrieve 210 sequential samples from 30 Covid-19 kidney allograft recipients (Baseline and 6 sequential samples from each patient) who developed reversible graft dysfunction; 210 sequential samples from 30 Covid-19 kidney allograft recipients who developed nonreversible graft dysfunction; and 30 Covid-19 kidney allograft recipients who did not develop graft dysfunction during the 3-months since Covid-19 diagnosis. RNA isolated from urinary cells will be reverse transcribed to cDNA and absolute copy numbers of CD3E mRNA, CXCL10 mRNA and 18S rRNA will be measured using customized PCR assays and urinary cell 3-gene signature score will be computed using a validated regression equation. The objective is to determine whether the urinary cell 3-gene scores in sequential samples anticipate those who develop nonreversible graft dysfunction rom those who develop reversible graft dysfunction.

我们寻求额外资金用于应对 SARS-CoV-2/COVID-19 爆发的研究，该研究范围属于我们正在进行的拨款 R37AI051652“用于安全最小化免疫抑制的生物分子标记。” 2020年3月13日至2020年4月20日，我们住院了39名SARS-CoV-2阳性同种异体肾移植受者，在这些患有 Covid-19 症状的患者中，有 20 名（51%）出现急性肾损伤（AKI）。截至 2020 年 5 月 15 日，仅 9 名患者因 AKI 导致的功能障碍恢复，11 名患者未恢复。无由于出血等活检相关并发症，进行了诊断性同种异体移植活检这一群体的情况可能更为严重，同时也为了限制医护人员接触 SARS 的可能性侵入性活检过程中出现 CoV-2 在没有进行诊断性活检的情况下，没有人接受抗排斥治疗。移植物功能障碍是可逆的还是不可逆的，在移植时无法预测。功能障碍诊断。来自免疫抑制减少的抗同种异体移植反应的动态。现有的临床分析人员无法捕获治疗方法，为了解决这些现有的挑战，我们。提出以下建议：具体目标 1. 对泌尿细胞进行 RNA 测序并进行研究在移植物功能障碍时确定的尿细胞转录组是否可以预测在诊断移植物功能障碍时收集同种异体移植物功能障碍的尿液并从中分离RNA。 30 例可逆性移植物功能障碍患者的 RNA；30 例不可逆性移植物功能障碍患者的 RNA；移植物功能障碍；以及自 Covid-19 起 3 个月内无移植物功能障碍的 30 名患者的 RNA 诊断将通过RNA测序和生物信息学进行，目的是确定是否存在尿毒症。在移植物功能障碍时确定的细胞转录组谱可预测移植物功能障碍区分可逆性移植物功能障碍和不可逆性移植物功能障碍。目标 2. 测量 Covid-19 肾脏的连续尿液样本中的尿细胞 3 基因特征评分同种异体移植受者的尿液将在基线时收集，并在 3 个月内每两周依次收集一次。 Covid-19 诊断我们将从 30 名 Covid-19 肾移植受者身上检索 210 个连续样本。第 210 章来自 30 名出现不可逆移植功能障碍的 Covid-19 同种异体肾移植受者的连续样本；以及 30 名 Covid-19 肾同种异体移植受者，他们在 3 个月内没有出现移植功能障碍 Covid-19 诊断。从尿细胞中分离的 RNA 将被逆转录为 cDNA 和绝对拷贝。 CD3E mRNA、CXCL10 mRNA 和 18S rRNA 的数量将使用定制的 PCR 检测进行测量，将使用经过验证的回归方程计算尿细胞 3 基因特征评分。确定连续样本中的尿细胞 3 基因评分是否预测那些发展不可逆性移植物功能障碍来自那些发生可逆性移植物功能障碍的人。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（4）

Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract.

DOI：
10.1038/s41467-018-04745-0
发表时间：
2018-06-20
期刊：
Nature communications
影响因子：
16.6
作者：
Burnham P;Dadhania D;Heyang M;Chen F;Westblade LF;Suthanthiran M;Lee JR;De Vlaminck I
通讯作者：
De Vlaminck I

Gut microbiota and tacrolimus dosing in kidney transplantation.

DOI：
10.1371/journal.pone.0122399
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Lee JR;Muthukumar T;Dadhania D;Taur Y;Jenq RR;Toussaint NC;Ling L;Pamer E;Suthanthiran M
通讯作者：
Suthanthiran M

Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.

DOI：
10.1371/journal.pone.0267704
发表时间：
2022
期刊：
PLOS ONE
影响因子：
3.7
作者：
Suryawanshi, Hemant;Yang, Hua;Lubetzky, Michelle;Morozov, Pavel;Lagman, Mila;Thareja, Gaurav;Alonso, Alicia;Li, Carol;Snopkowski, Catherine;Belkadi, Aziz;Mueller, Franco B.;Lee, John R.;Dadhania, Darshana M.;Salvatore, Steven P.;Seshan, Surya, V;Sharma, Vijay K.;Suhre, Karsten;Suthanthiran, Manikkam;Tuschl, Thomas;Muthukumar, Thangamani
通讯作者：
Muthukumar, Thangamani

Sex and Kidney Transplantation: Why Can't a Woman Be More Like a Man?

性与肾移植：为什么女人不能更像男人？

DOI：
10.1681/asn.2017060657
发表时间：
2017
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
0
作者：
August,Phyllis;Suthanthiran,Manikkam
通讯作者：
Suthanthiran,Manikkam

Gut microbiota dysbiosis and diarrhea in kidney transplant recipients.

DOI：
10.1111/ajt.14974
发表时间：
2019-03
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
0
作者：
Lee JR;Magruder M;Zhang L;Westblade LF;Satlin MJ;Robertson A;Edusei E;Crawford C;Ling L;Taur Y;Schluter J;Lubetzky M;Dadhania D;Pamer E;Suthanthiran M
通讯作者：
Suthanthiran M