BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10589980
• 负责人: Arun Kumar Rishi
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589980
• 关键词: Adriamycin PFS; Age; American Cancer Society; Angiotensins; Apoptosis; Apoptosis Regulation Gene; Area; Atherosclerosis; Attenuated; Award; Behavioral Mechanisms; Binding; Biological; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Epithelial Cells; Cancer Cell Growth; Cancer Etiology; Carcinogens; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Cell model; Cessation of life; Chemicals; Chemoresistance; Chronic; Chronic Disease; Cisplatin; Clinic; Collaborations; Coupled; Cyprinus carpio; DNA Sequence Alteration; Depressed mood; Development; Diagnosis; Disease; Drug resistance; Endothelin; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Etoposide; Exposure to; Female; Formulation; Foundations; Funding; Gefitinib; General Population; Goals; Growth; Health; Healthcare; Healthcare Systems; Heart Diseases; High Prevalence; Hormones; Human; Hypertension; Incidence; Individual; Induction of Apoptosis; Inflammation; Kidney; Knowledge; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Medical Care Costs; Mental Depression; Military Personnel; Mission; Modality; Modeling; Molecular; Morbidity - disease rate; Mutation; Myocardial Infarction; Neurons; Non-Small-Cell Lung Carcinoma; Occupational Exposure; Pathway interactions; Phosphotransferases; Prevalence; Process; Productivity; Proteins; Quality of life; Regulation; Renal Artery Stenosis; Renal carcinoma; Renovascular Hypertension; Research; Research Activity; Research Personnel; Research Project Grants; Resistance; Rheumatoid Arthritis; Risk; Rodent Model; Scientist; Seminal; Services; Signal Induction; Signal Transduction; Socioeconomic Status; Stimulus; Stress; Stroke; Therapeutic; Therapeutic Uses; Treatment Efficacy; Treatment Failure; Vasopressins; Veterans; Woman; anti-cancer; anti-cancer therapeutic; anticancer research; behavioral response; biological adaptation to stress; cancer cell; cardiovascular risk factor; career; cell growth; chemotherapy; combat; depression model; design; effective therapy; falls; genotoxicity; healing; human old age (65+); improved; improved outcome; in vivo; inhibitor; kidney vascular structure; knockout gene; lung cancer cell; malignant breast neoplasm; men; mimetics; mortality; mortality risk; mutant; nano; novel; novel therapeutic intervention; pre-clinical; preclinical study; prevent; productivity loss; programs; refractory cancer; service member; small molecule; smoking prevalence; success; targeted treatment; therapy outcome; therapy resistant; triple-negative invasive breast carcinoma

Inflammation is the body's attempt at self-protection to remove harmful stimuli and begin the healing process. Chronic inflammation can eventually cause several diseases and conditions, including cancers, rheumatoid arthritis, atherosclerosis, and plays a role in heart disease. The overarching goals of nominee’s research involve elucidating molecular underpinnings of cell growth/survival and death/apoptosis with particular reference to cancer, atheroscleroscosis, and cardiovascular hypertension. The American Cancer Society estimates highest percent of new cases and mortality resulting from lung and breast cancers in females, while prostate and lung cancers account for highest percentage of new cases and associated mortality among men. Overall incidence rates and mortality due to lung and breast cancers have decreased over last decade partly due to advances in diagnosis and therapeutics, particularly targeted therapeutics for a number of cancers including the non-small cell lung cancers (NSCLCs). However, adaptive genetic alterations and mutations in cancers contribute to therapy failures and relapses in clinic occur that often result in emergence of resistant, hard to treat disease, and warrant development of new therapeutic strategies to overcome drug resistance and improve therapeutic outcomes. By utilizing a functional gene-knockout approach the nominee identified a novel, apoptosis inducing protein termed CARP-1/CCAR1 (J. Biol. Chem. 278: 33422-33435, 2003). CARP-1 regulates apoptosis signaling induced by diverse therapeutics such as Adriamycin, Etoposide, and Gefitinib (Oncotarget 6(9): 6499- 510, 2015). Following CARP-1 discovery, the nominee conducted a chemical-biological approach to identify novel small molecule CARP-1 Functional Mimetic (CFMs) compounds (J. Biol. Chem. 286 (44): 38000-38017, 2011). CFMs inhibit growth of therapy-resistant triple-negative breast cancers (TNBC) and non-small cell lung cancers (NSCLCs) in part by inducing CARP-1-dependent apoptosis (Oncotarget, 7(45): 73370–73388, 2016; 8(62):104928-104945, 2017; 9(51): 29680-29697, 2018). During RCS funding, nominee made a fundamental observation that CARP-1 interacts with NF-κB kinase subunit gamma (IKKγ). This interaction functions to activate NF-κB-dependent cell survival and growth in genotoxic chemotherapy-treated cancer cells (J. Biol. Chem. 295: 3532-3552, 2020). Targeting of IKKγ-CARP-1 binding prevents therapy-induced NF-κB activation. On the basis of this finding nominee discovered new compounds, termed selective NF-κB inhibitors (SNIs), that target IKKγ-CARP-1 binding to attenuate therapy-induced survival pathways and enhance efficacy of cisplatin in preclinical tumor models of breast and renal cancers. Given that cisplatin is widely used anti-cancer therapeutic in BRCA-mutant breast, non-small cell lung, and kidney cancers, SNI compounds will provide a novel avenue to improve chemotherapy efficacy and attenuate emergence of drug-resistant cancers. The nominee’s long-term goal is to elucidate molecular mechanisms of therapy resistance in TNBC and NSCLCs, and utilize this knowledge to develop novel, safer and effective anti-cancer modalities. In this context CFMs and SNIs or their derivatives are anticipated to facilitate development of strategies for effective treatment of TNBC, NSCLCs, and other cancers in the VA healthcare system and beyond. Prevalence of atherosclerotic reno-vascular hypertension is rising. Renal artery stenosis occurs in 28% of veterans undergoing cardiac catheterization with a greater than 3-fold risk in those over age 65. There is an alarming burden of cardiovascular and renal morbidity and mortality with attendant increases in direct medical costs, loss of productivity and quality of life in our Veterans with hypertension. The nominee continues to have a productive collaboration with Detroit VA clinician-scientist to study the molecular and behavioral mechanisms of the angiotensin-endothelin signaling in Reno-vascular model. In RCS funding period, nominee served as a co- investigator of the two VA funded Merit applications that investigated mechanisms of reno-vascular hypertension.

炎症是人体自我保护的一种尝试，目的是清除有害刺激并开始愈合过程。 慢性炎症最终会导致多种疾病和状况，包括癌症、类风湿 关节炎、动脉粥样硬化，并在心脏病中发挥作用。被提名者研究的首要目标包括 阐明细胞生长/存活和死亡/凋亡的分子基础，特别是 癌症、动脉粥样硬化和心血管高血压。 美国癌症协会估计，肺癌导致的新病例和死亡率最高 女性中的乳腺癌，而前列腺癌和肺癌在新病例中所占比例最高 以及相关的男性死亡率。肺癌和乳腺癌的总发病率和死亡率有 在过去十年中下降的部分原因是诊断和治疗方面的进步，特别是有针对性的 治疗多种癌症，包括非小细胞肺癌(NSCLC)。但是，自适应 癌症中的基因改变和突变导致治疗失败和临床上经常发生的复发 导致耐药、难以治疗的疾病的出现，并需要开发新的治疗策略 克服耐药性，提高治疗效果。 通过利用功能基因敲除方法，被提名者确定了一种新的诱导细胞凋亡的方法 命名为Carp-1/CCAR1的蛋白质(J.Biol.化学。2003年：33422-33435)。CARP-1对细胞凋亡的调控作用 阿霉素、依托泊苷和吉非替尼等不同疗法诱导的信号转导(肿瘤靶标6(9)：6499- 510,2015)。在发现Carp-1之后，被提名者进行了化学-生物学方法来鉴定 新型小分子CARP-1功能模拟(CFMS)化合物(J.Biol.化学。电话：38000-38017； 2011年)。CFM抑制耐药三阴性乳腺癌和非小细胞肺癌的生长 癌症(NSCLC)部分通过诱导依赖于Carp-1的细胞凋亡(OncoTarget，7(45)：73370-73388,2016年； 8(62)：104928-104945,2017年；9(51)：29680-29697,2018年)。在RCS资助期间，被提名者做出了一个基本的 观察到CARP-1与核因子-κB激酶亚单位γ(IKKγ)相互作用。这种交互作用可用于 激活依赖于NF-κB的细胞在基因毒性化疗治疗的癌细胞中的生存和生长(J.Biol. 化学。295：3532-3552,2020)。靶向IKKγ-CARP-1结合可阻止治疗诱导的NF-κB激活。 在这一发现的基础上，被提名的人发现了新的化合物，称为选择性核因子-κB抑制剂(SNI)， 靶向IKKγ-CARP-1结合减弱化疗诱导的生存通路并增强顺铂的疗效 乳腺癌和肾癌的临床前肿瘤模型。鉴于顺铂被广泛应用于抗癌治疗 在BRCA突变的乳腺癌、非小细胞肺癌和肾癌中，SNI化合物将提供一种新的途径 提高化疗疗效，减少耐药癌症的出现。被提名人的长期任期 目的是阐明TNBC和NSCLC耐药的分子机制，并利用这一机制 开发新的、更安全和有效的抗癌方法的知识。在此上下文中，CFM和SNI或其 预计衍生品将有助于制定有效治疗TNBC、NSCLC和 退伍军人医疗保健系统及其他领域的其他癌症。 动脉粥样硬化性肾血管高血压的患病率正在上升。肾动脉狭窄的发生率为28% 65岁以上的退伍军人接受心导管术的风险是前者的3倍以上。有一个 心血管和肾脏发病率和死亡率的惊人负担，伴随着直接医疗费用的增加 我们患有高血压的退伍军人的成本、生产力损失和生活质量。被提名者继续拥有 与底特律退伍军人事务部临床医生兼科学家富有成效地合作，研究糖尿病的分子和行为机制 血管紧张素-内皮素信号在肾血管模型中的作用。在RCS资助期内，被提名人担任联席- 两项由退伍军人事务部资助的研究肾血管性高血压机制的研究人员。