BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10293561
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293561
• 关键词: Adriamycin PFS; Affect; Age; American Cancer Society; Angiotensins; Apoptosis; Apoptosis Regulation Gene; Area; Atherosclerosis; Attenuated; Award; Binding; Biological; Brain; Breast; Breast Cancer Cell; Breast Epithelial Cells; Cancer Cell Growth; Cancer Etiology; Carcinogens; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Cell model; Cells; Cessation of life; Chemicals; Chemoresistance; Chemotherapy-Oncologic Procedure; Chronic; Chronic Disease; Clinic; Clinical; Collaborations; Couples Therapy; DNA Sequence Alteration; Depressed mood; Development; Diagnosis; Disease; Drug resistance; Endothelin; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Etoposide; Exposure to; Female; Formulation; Foundations; Funding; Future; Gefitinib; General Population; Goals; Growth; Health; Healthcare; Healthcare Systems; Heart Diseases; High Prevalence; Hormones; Human; Hypertension; Incidence; Individual; Inflammation; Kidney; Knowledge; Laboratories; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medical Care Costs; Mental Depression; Military Personnel; Mineralocorticoid Receptor; Mission; Modality; Modeling; Molecular; Morbidity - disease rate; Mutation; Myocardial Infarction; Nano delivery; Neurons; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Occupational Exposure; Oncogenic; Patients; Play; Prevalence; Process; Proteins; Publications; Quality of life; Receptor Protein-Tyrosine Kinases; Regulation; Relapse; Renal Artery Stenosis; Renovascular Hypertension; Research; Research Activity; Research Personnel; Research Project Grants; Resistance; Rheumatoid Arthritis; Risk; Rodent Model; Role; Scientist; Seminal; Services; Signal Transduction; Socioeconomic Status; Steroids; Stimulus; Stress; Stroke; Systemic hypertension; Testing; Therapeutic; Thyroid Gland; Time; Treatment Failure; Tyrosine Kinase Inhibitor; Variant; Vasopressins; Veterans; Woman; Women' s Health; acute stress; anti-cancer; behavioral response; biological adaptation to stress; cancer cell; cardiovascular risk factor; career; cell growth; combat; depression model; design; effective therapy; falls; healing; heart function; human old age (65+); improved; improved outcome; in vivo; kidney vascular structure; knockout gene; lapatinib; malignant breast neoplasm; meetings; men; mimetics; mortality; mortality risk; nano; novel; novel therapeutic intervention; paraventricular nucleus; preclinical study; productivity loss; programs; receptor; research and development; response; 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 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 therapeutic modalities, 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 chemotherapeutics such as Adriamycin, Etoposide, and Gefitinib (reviewed by nominee in 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 diverse cancer cells including therapy-resistant triple-negative breast cancers (TNBC) and non-small cell lung cancers (NSCLCs) in part by binding with CARP-1, causing elevated levels of CARP-1 and apoptosis (Oncotarget, 2016, in press). The nominee’s long-term goal is to elucidate molecular mechanisms of therapy resistance in cellular models of resistant TNBC and NSCLCs, and utilize this knowledge to develop novel, safer and effective anti-cancer modalities. In this context CFMs or their derivatives are anticipated to have clinical utility, and could provide novel means to develop future strategies for effective treatment of TNBC, NSCLCs, and other cancers in the VA healthcare system and beyond. Hypertension is a major health issue in the U.S., and the prevalence of atheros clerotic 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. Nonetheless, 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 has a productive collaboration with Detroit VA clinician- scientist to study the molecular mechanisms of the hypertension. Since CARP-1 is also a co-activator of the signaling by the steroid-thyroid receptors (Molecular Cell 31: 510-519, 2008), and with the knowledge that mineralocorticoid receptor is known to play an important role in reno-vascular signaling, a potential overlap of CARP-1 functions in this model was envisioned. Moreover, the fact that anti-cancer chemotherapies often affect cardiac functions in patients, the nominee initiated this collaboration to study overlapping as well as specific, perhaps, novel aspects of the angiotensin-endothelin signaling in Reno-vascular model. Although this hypothesis has yet to tested, the nominee has thus far contributed in publication of an abstract in a national meeting and is serving as a co-investigator of the two current VA funded Merit applications that focus on investigating 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 涉及阐明细胞生长/存活和死亡/凋亡的分子基础 参考癌症、动脉粥样硬化和心血管高血压。 美国癌症协会估计，肺癌和肺癌导致的新病例和死亡率最高 女性乳腺癌，而前列腺癌和肺癌在新病例中所占比例最高， 男性的相关死亡率。肺癌和乳腺癌的总发病率和死亡率有 在过去十年中有所减少，部分原因是诊断和治疗方式的进步，特别是 一些癌症的靶向治疗，包括非小细胞肺癌(NSCLC)。然而， 癌症中的适应性基因改变和突变导致治疗失败和临床复发 这往往会导致出现抗药性、难以治疗的疾病，并需要开发新的治疗方法 克服耐药性和改善治疗结果的战略。 通过利用功能基因敲除方法，被提名者确定了一种新的凋亡诱导蛋白 命名为CARP-1/CCAR1(J.Biol.化学。2003年：33422-33435)。CARP-1调控细胞凋亡信号转导 由不同的化疗药物诱导，如阿霉素、依托泊苷和吉非替尼(由 肿瘤目标6(9)：6499-510,2015)。在发现Carp-1之后，被提名者进行了一项化学-生物学研究 鉴定新的小分子CARP-1功能模拟(CFMS)化合物的方法(J.Biol.化学。286 (44)：38000-38017,2011年)。CFM抑制多种癌细胞生长，包括耐药三重阴性 乳腺癌(TNBC)和非小细胞肺癌(NSCLC)部分通过与CARP-1结合，导致 CARP-1水平升高和细胞凋亡(OncoTarget，2016，印刷中)。被提名人的长期目标是 在耐药的TNBC和NSCLC细胞模型中阐明耐药的分子机制 利用这些知识开发新的、更安全和有效的抗癌方法。在这种情况下，CFM或其 衍生物有望具有临床用途，并可能为开发未来的策略提供新的手段。 用于有效治疗退伍军人管理局医疗系统内外的TNBC、NSCLC和其他癌症。 在美国，高血压是一个主要的健康问题，动脉粥样硬化性肾血管疾病的流行 高血压正在上升。28%接受心导管置入术的退伍军人发生肾动脉狭窄 65岁以上人群的风险是前者的3倍以上。尽管如此，心血管疾病和高血压的负担令人担忧。 肾脏发病率和死亡率随之而来的直接医疗费用增加，生产力和质量损失 患有高血压的退伍军人的生活。这位被提名人与底特律退伍军人管理局临床医生进行了富有成效的合作- 科学家将研究高血压的分子机制。由于CARP-1也是该蛋白的共同激活因子 通过类固醇-甲状腺受体发出信号(分子细胞31：510-519,2008)，并了解到 已知盐皮质激素受体在肾血管信号转导中发挥重要作用，其潜在的重叠 对CARP-1在该模型中的作用进行了设想。此外，抗癌化疗往往 影响患者的心功能，被提名者发起了这一合作，以研究重叠以及 在肾血管模型中，血管紧张素-内皮素信号的特定的，也许是新的方面。虽然这件事 假设还没有得到检验，到目前为止，被提名者已经在一份全国性的 会议，并担任退伍军人管理局资助的两个当前奖励申请的联合调查员，这两个申请的重点是 探讨肾血管性高血压的发病机制。