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.

根据美国人口普查局的数据，2018年美国退伍军人人数约为19.9人 每 10 人中有 9 人是男性，其中 33% 年龄在 50-69 岁之间，这是最高的年龄组。 VA 中心癌症登记处显示，前列腺癌 (PCa) 的风险最高。 男性退伍军人中经常诊断出的癌症，占约 50,000 种癌症的 30% 以上 人们越来越担心在诊断过程中环境和/或职业接触金属离子。 服役和服役后会增加退伍军人的前列腺癌风险。 无机砷（iAs）被列为致癌物，而铅（Pb）则是人类潜在的致癌物。 暴露是服兵役的一种已知危险，而有关 iAs 暴露的数据尚不明确。 退伍军人广泛接触这些金属离子可能是通过吸入、摄入和 皮肤吸收来自燃烧油田和废物处理燃烧坑的有毒烟雾。砷和/或铅暴露。 已被认为是 PCa 的潜在危险因素，但其潜在机制在很大程度上尚不清楚。 小型临床研究，我们发现 PCa 患者尿液中 iAs 和 Pb 水平显着升高 与对照组相比，使用我们新的 2 次打击动物模型，我们发现接触 iAs 或 Pb 会增加 (1) PCa。 体内风险和（2）从治疗动物中分离出的前列腺上皮干细胞样细胞（PrESLC）的能力 在软琼脂中形成菌落，这是细胞转化的标志，在该动物模型中，进行为期 1 个月的金属处理。 随后化学致癌剂治疗显着增加PCa和癌前病变的发生率 经 iAs 处理的小鼠中的损伤，与经 Pb 处理的动物中的相似趋势，重要的是，单细胞 RNAseq 分析。 揭示 Pb 与具有上皮谱系的 PrESLC 亚群的扩张有关 标记物进入基质样致癌细胞，而 iAs 与一种罕见、独特的细胞的出现有关。 类似于“癌症”干细胞的致癌性 PrESLC 亚群 该提案将检验以下假设： iAs 和/或 Pb 失调亚群中特定且可能不同的信号传导途径 PrESLC 会引发或增加前列腺癌变的风险这是一个未经检验的假设。 提出了两个目标 1：确定。 使用 PCa 形成的肾移植模型研究金属处理的 PrESLC 体内的致癌潜力。 将评估金属对免疫缺陷宿主小鼠体内 PCa 形成的影响，无论是使用还是 目标 2：用金属特异性转录组表征干细胞样细胞。 我们将使用单细胞 RNAseq 和可视化信息学来识别独特的基因特征。 我们的目标是描述 PrESLC 群体中金属诱导的癌症干细胞的稀有亚群。 应用这些基因特征通过 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图谱 PCa 数据和其他在线数据库来实现准确的 对 PrESLC 的主要、罕见和异质亚型进行分类，以深入了解金属致癌作用。 拟议工作的结果可能会解决与职业和部署后暴露相关的问题 并扩展我们对干细胞生物学的了解。成功完成这些研究可能会导致 制定新的 PCa 预防和治疗策略，以减少不必要的接触。 金属离子可以作为针对特定药物预防 PCa 的有效策略。 干细胞亚群可用作预防前列腺癌早期发展并减缓前列腺癌的治疗选择 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 这个社区内外的残疾。