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Characterization of B Lymphocyte Deficiency in Pediatric Sickle Cell Disease

儿童镰状细胞病 B 淋巴细胞缺乏的特征

基本信息

批准号：
10641800
负责人：
Venee N Tubman
金额：
$ 16.32万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641800
关键词：
5 year old ANXA5 gene Abnormal Cell Acute Africa Africa South of the Sahara Age Apoptosis B cell differentiation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes BCL2 gene Bacteremia CASP3 gene Cessation of life Chest Child Childhood Clinical Coculture Techniques Custom Cytokine Signaling Development Disease Enrollment Environment Enzyme-Linked Immunosorbent Assay Exposure to Funding Goals Histopathology Human Herpesvirus 4 Immune Immune response Immune system Impairment In Vitro Infection Inflammatory Innate Immune Response Intrinsic factor Investigation Kinetics Life Lymphocyte Count Malaria Marginal Zone B-Lymphocyte Measures Memory B-Lymphocyte Mentorship Modeling Monitor Morbidity - disease rate Natural Immunity Osteomyelitis Patients Plasma Cells Plasmodium Population Proliferating Research Research Personnel Risk Assessment Risk Reduction Role Sampling Serum Sickle Cell Anemia Spleen System T-Lymphocyte Tanzania Texas Therapeutic Tissue Banks Tissues Training Viral Virus Work biomarker development clinical phenotype cohort cytokine driver mutation experience humoral immunity deficiency immune function infancy infection risk inflammatory milieu insight mortality new therapeutic target pathogen patient stratification peripheral blood programs risk stratification sample collection therapeutic biomarker therapeutic target tool

项目摘要

PROJECT SUMMARY Infections are frequent complications in sickle cell disease (SCD), occurring in up to 45% of patients. In Africa, where up to 90% of children with SCD die by age 5 years, many of these deaths are attributed to infection. In SCD, the spleen is damaged in infancy and results in marginal zone B cell deficiency. The clinical implications of B cell deficiency in SCD are not fully understood and requires investigating both disease-intrinsic and - extrinsic modifiers of B cell subsets. In this investigation, I will quantify B cell subsets in children with and without SCD in Texas and in Tanzania, investigate mechanisms of B cell deficiency, and compare them to important clinical endpoints. Aim 1: Characterize mechanisms of MZB deficiency in SCD. Hypotheses: There is a difference in the development, survival, and function of B cells from SCD and non-SCD subjects due to B-cell intrinsic factors. Differences in B cell populations may be due to differences in kinetics of differentiation and proliferation and/or survival. To examine differentiation and proliferation, I will measure the efficiency of differentiation of transitional B cells from SCD and non-SCD donors into MZBs, and MZBs into plasma cells using an in vitro B cell co-culture system. To examine survival, I will measure the rate of apoptosis and expression of markers of apoptosis (e.g. annexin V, caspase 3/9, BCL2) in native and culture-derived MZBs in culture. Aim 2: Determine the effect of the microenvironment of the spleen in SCD on B cells. Hypothesis: Extrinsic factors such as the inflammatory environment in SCD impair B cell development, survival, and function. To examine the effect of the microenvironment on B cells in culture, I will culture non-SCD B cells in media supplemented with SCD serum or spleen extract. To investigate which components of the extract impact B cells, I will develop a cytokine profile for the extract and serum using multiplex ELISA. Aim 3: Determine whether low MZB is associated with infectious and inflammatory complications of SCD. Hypothesis: Life-threatening infections in SCD are more common among children with severe MZB deficiency. To determine whether B-cell tropic viruses have a confounding effect on MZB number, I will measure immune response to EBV and malaria using a custom multiplex ELISA panel. To determine whether infectious complications are associated with more severe MZB deficiency in SCD, I will compare MZB among children with and without complications such as acute chest, osteomyelitis, or bacteremia. Despite a shared driver mutation, the clinical phenotype in SCD is highly variable. Together, the studies in this proposal will overcome critical barriers to risk-stratifying patients for infectious and inflammatory complications of SCD. Increased insights into how SCD catalyzes B cell deficiency may help identify novel therapeutic targets or biomarkers to mitigate the impact of infections on SCD. My central hypothesis is that B cell abnormalities contribute to morbidity and mortality in children with SCD.

项目总结

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regional anesthesia for sickle cell disease vaso-occlusive crisis: A single-center case series.

DOI：
10.1002/pbc.29695
发表时间：
2022-06
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
通讯作者：

Allele-Specific Recombinase Polymerase Amplification to Detect Sickle Cell Disease in Low-Resource Settings.

DOI：
10.1021/acs.analchem.0c04191
发表时间：
2021-03-23
期刊：
Analytical chemistry
影响因子：
7.4
作者：
Natoli ME;Chang MM;Kundrod KA;Coole JB;Airewele GE;Tubman VN;Richards-Kortum RR
通讯作者：
Richards-Kortum RR

Unique Hemoglobinopathy Pattern Following Treatment with Voxelotor.

Voxelotor 治疗后独特的血红蛋白病模式。

DOI：
发表时间：
2023
期刊：
Annals of clinical and laboratory science
影响因子：
0.8
作者：
Poventud-Fuentes,Izmarie;Portillo,TaniaPlatero;Olayinka,Lily;Marcogliese,AndreaN;Tubman,VenéeN;Devaraj,Sridevi
通讯作者：
Devaraj,Sridevi

Determinants of retention in care of newborns diagnosed with sickle cell disease in Liberia: Results from a mixed-methods study of caregivers.

利比里亚诊断出患有镰状细胞病的新生儿保留的决定因素：由治疗者进行混合方法的结果。