BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10589966
• 负责人: Shuk-Mei Ho
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589966
• 关键词: Accounting; Address; Adsorption; Adult; Afghanistan; Agar; Androgen Suppression; Animal Model; Animals; Anniversary; Aromatic Polycyclic Hydrocarbons; Arsenic; Award; Barker Hypothesis; Biological Markers; Body Fluids; Canada; Cancer Patient; Cancer Research Project; Carcinogens; Cell Death; Cell Separation; Cells; Censuses; Chemicals; Childhood Asthma; Chronic Disease; Classification; Clinical Research; Communities; Data; Databases; Department of Defense; Dermal; Development; Diagnostic; Disease; Disparity; Drug Targeting; ESR1 gene; Educational workshop; Elderly; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Exposure; Environmental Health; Environmental and Occupational Exposure; Epidemiology; Epigenetic Process; Epithelium; Estrogen Receptor beta; Estrogens; European Union; Exposure to; Funding; GPER gene; General Population; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Grant; Health; High-Risk Cancer; Hormonal Carcinogenesis; Human; Immune; Incidence; Influentials; Informatics; Ingestion; Inhalation; International; International Agencies; Intervention; Ions; Iraq; Joints; Kidney Transplantation; Knowledge; Lead; Lead levels; Lesion; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical Research; Metal Carcinogenesis; Metal exposure; Metals; Methylation; Military Personnel; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Environmental Health Sciences; National Toxicology Program; Occupational; Occupational Exposure; Occupations; Ohio; Oils; Oncogenic; Paper; Participant; Peer Review; Policies; Population; Productivity; Prostate; Prostatic Epithelium; Protein Isoforms; Publishing; Refuse Disposal; Reporting; Research; Risk; Risk Factors; Role; Safety; Scientist; Seminal; Signal Pathway; Smoke; Societies; Source; Strategic Planning; Testing; The Cancer Genome Atlas; Therapeutic; Toxicant exposure; Toxicology; Translating; Translations; Tumor Suppressor Proteins; Umbilical Cord Blood; United States; United States Department of Veterans Affairs; United States National Institutes of Health; Urine; Urology; Veterans; Visualization; Woman; Work; age group; anticancer research; bisphenol A; burn pit; cancer diagnosis; cancer stem cell; carcinogenesis; carcinogenicity; career; castration resistant prostate cancer; chemical carcinogen; comparison control; consumer behavior; data registry; disability; disorder risk; early life exposure; environmental toxicology; epigenomics; epithelial stem cell; experience; genetic signature; hazard; high risk; hormone regulation; improved; in vivo; indexing; insight; lead exposure; male; member; metaplastic cell transformation; military service; military veteran; mouse model; neoplasm registry; novel; novel strategies; precision medicine; premalignant; prevent; programs; promoter; prostate cancer cell; prostate cancer model; prostate cancer prevention; prostate cancer risk; prostate carcinogenesis; public health intervention; public health research; single-cell RNA sequencing; specific biomarkers; stem cell biology; stem cell population; stem cells; stem-like cell; symposium; toxicant; transcriptomics; trend; understudied cancer; urinary; urologic

According to the United States (US) Census Bureau, the number of veterans in the US in 2018 was around 19.9 million. Nine out of 10 were males, and 33% were between 50-69 years old, an age group that is at the highest risk for prostate cancer (PCa). The VA Central Cancer Registry consistently shows that PCa is the most frequently diagnosed cancers among male veterans, accounting for >30% of the approximately 50,000 cancer diagnoses. There is growing concern that environmental and/or occupational exposure to metal ions during deployment and post-deployment increases PCa risk in veterans. The International Agency for Cancer Research classified inorganic arsenic (iAs) as a carcinogen, while lead (Pb) is a potential carcinogen in humans. Pb exposure is a known hazard of military service, while data for iAs exposure is less well-established. Further, wide-spread exposure to these metal ions in veterans could be mediated through inhalation, ingestion, and dermal adsorption of toxic smoke from burning oil fields and waste disposal burn-pits. iAs and/or Pb exposure have been considered potential risk factors for PCa, but the underlying mechanism is largely undefined. In a small clinical study, we found that iAs and Pb levels were significantly higher in the urine of PCa patients compared to controls. Using our new 2-hit animal model, we found that exposure to iAs or Pb increased (1) PCa risk in vivo and (2) the ability of prostate epithelial stem-like cells (PrESLCs) isolated from treated animals to form colonies in soft agar, a hallmark of cellular transformation. In this animal model, a 1-month metal treatment followed by chemical carcinogen treatment significantly increased the incidence of PCa and pre-cancerous lesions in iAs-treated mice, with similar trends in Pb-treated animals. Importantly, single-cell RNAseq analyses revealed that Pb was associated with the expansion of a subpopulation of PrESLCs with epithelial lineage markers into stroma-like oncogenic cells, while iAs was associated with the emergence of a rare, unique subpopulation of oncogenic PrESLCs similar to “cancer” stem cells. This proposal will test the hypothesis that iAs and/or Pb dysregulate specific, and likely different, signaling pathways in subpopulations of PrESLCs to initiate or increase the risk of carcinogenesis in the prostate. This is an untested hypothesis in the field of prostate carcinogenesis and in military veterans’ health. Two Aims are proposed. Aim 1: Determine the carcinogenic potential of metal treated PrESLCs in vivo using a renal grafting model of PCa formation. We will evaluate the effects of metals on the formation of PCa in vivo in immune-deficient host mice, either with or without chemical induction of PCa. Aim 2: Characterize stem-like cells with metal-specific transcriptomic signatures. We will use single-cell RNAseq and visualization informatics to identify the unique gene signatures that characterize rare subpopulations of metal-induced cancer stem cells within the PrESLC population. We aim to apply these gene signatures to enrich rare subpopulations by FACS and evaluate their carcinogenic potential. We will also leverage The Cancer Genome Atlas PCa data and other online databases to enable accurate classification of major, rare, and heterogeneous subtypes of PrESLCs to gain insights into metal carcinogenesis. Findings from the proposed work may address questions related to occupational and post-deployment exposure and expand our knowledge of stem cell biology. Successful completion of these studies may lead to the development of new PCa prevention and therapeutic strategies. Plans to reduce unnecessary exposure to those metal ions can be justified and implemented as effective strategies for PCa prevention. Drugs targeting specific subpopulations of stem cells may be used as therapeutic options to prevent early PCa development and slow progression. When applied to veterans, the results of this study may save lives, improve health, and decrease disabilities in this community and beyond.

根据美国（美国）人口普查局的数据，2018年美国的退伍军人人数约为19.9 百万。男性中有九分之一是男性，而33％的年龄在50-69岁之间，一个年龄段最高的年龄段 前列腺癌（PCA）的风险。 VA中央癌症注册表始终表明PCA是最大的 在男性退伍军人中经常被诊断出癌症，占约50,000个癌症的30％ 诊断。越来越担心的是，环境和/或占据金属离子的暴露 部署和部署后增加了退伍军人的PCA风险。国际癌症研究机构 分类为无机砷（IAS）作为致癌物，而铅（PB）是人类的潜在致癌物。 pb 暴露是已知的兵役危害，而IAS暴露数据的建立不足。更远， 可以通过吸入，摄入和 真皮增加了燃烧的油田和废物处理燃烧坑来吸收有毒的烟雾。 IAS和/或PB暴露 已被认为是PCA的潜在危险因素，但基本机制在很大程度上是不确定的。在 小型临床研究，我们发现PCA患者尿液中的IAS和PB水平明显更高 与对照组相比。使用我们新的2次命中动物模型，我们发现暴露于IAS或PB增加（1）PCA 风险在体内和（2）从治疗的动物分离到的前列腺上皮样细胞（Preslc）的能力 在软琼脂中形成菌落，这是细胞转化的标志。在此动物模型中，1个月的金属处理 然后进行化学致癌物处理显着增加了PCA和癌前的发生率 IAS治疗的小鼠的病变，PB处理的动物具有相似的趋势。重要的是，单细胞RNASEQ分析 揭示了Pb与具有上皮谱系的Preslc的亚群的扩展有关 标记在基质状的致癌细胞中，而IAS与罕见，独特的出现有关 与“癌症”干细胞相似的致癌性主体的亚群。该提议将检验以下假设 IAS和/或PB在亚群中的特异性和/或可能不同的信号通路 Preslcs启动或增加前列腺中癌变的风险。这是一个未经测试的假设 在前列腺癌变和退伍军人健康领域。提出了两个目标。目标1：确定 使用PCA形成的肾脏移植模型，金属处理过的Preslc的致癌潜力。我们 将评估金属对免疫缺陷宿主小鼠体内PCA形成的影响，无论是或 没有化​​学诱导PCA。 AIM 2：用金属特异性转录组来表征茎状细胞 签名。我们将使用单细胞RNASEQ和可视化信息来识别独特的基因特征 这表征了PRESLC种群中金属诱导的癌症干细胞的罕见亚群。我们的目标 应用这些基因特征以通过FACS富集稀有亚群，并评估其致癌潜力。 我们还将利用癌症基因组ATLAS PCA数据和其他在线数据库来准确 PRERLC的主要，罕见和异质亚型的分类，以了解金属致癌的见解。 拟议工作的发现可能解决与职业和部署后有关的问题 并扩展我们对干细胞生物学的了解。这些研究的成功完成可能会导致 开发新的PCA预防和治疗策略。计划减少不必要的接触 金属离子可以作为预防PCA的有效策略合理并实施。针对特异性的药物 干细胞的亚群可以用作预防早期PCA发展和缓慢的治疗选择 进展。当应用于退伍军人时，这项研究的结果可能会挽救生命，改善健康并减少 这个社区及以后的残疾。