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.

炎症是身体试图进行自我保护，以消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病症，包括癌症、类风湿病 关节炎、动脉粥样硬化，并在心脏病中发挥作用。被提名者研究的总体目标 涉及阐明细胞生长/存活和死亡/凋亡的分子基础，特别是 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，由肺和癌症引起的新病例和死亡率最高百分比 女性乳腺癌，而前列腺癌和肺癌在新发病例中所占比例最高 男性的相关死亡率。肺癌和乳腺癌的总体发病率和死亡率 过去十年下降的部分原因是诊断和治疗方式的进步，特别是 针对包括非小细胞肺癌（NSCLC）在内的多种癌症的靶向治疗。然而， 癌症的适应性遗传改变和突变导致临床治疗失败和复发 这通常会导致出现耐药性、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策略。 通过利用功能性基因敲除方法，被提名者发现了一种新型的细胞凋亡诱导蛋白 称为 CARP-1/CCAR1 (J. Biol. Chem. 278: 33422-33435, 2003)。 CARP-1 调节细胞凋亡信号 由多种化疗药物诱导，如阿霉素、依托泊苷和吉非替尼（由提名人审查） Oncotarget 6(9): 6499-510, 2015)。在 CARP-1 发现之后，被提名者进行了化学-生物学研究 鉴定新型小分子 CARP-1 功能模拟 (CFM) 化合物的方法 (J. Biol. Chem. 286 （44）：38000-38017，2011）。 CFM 抑制多种癌细胞的生长，包括治疗耐药的三阴性癌细胞 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 年，待出版）。被提名者的长期目标是 阐明耐药 TNBC 和 NSCLC 细胞模型中治疗耐药的分子机制，以及 利用这些知识开发新颖、更安全和有效的抗癌方法。在这种情况下，CFM 或​​其 预计衍生品具有临床实用性，并可以提供制定未来策略的新方法 用于有效治疗 VA 医疗系统及其他地区的 TNBC、NSCLC 和其他癌症。 高血压是美国的一个主要健康问题，动脉粥样硬化性肾血管疾病的患病率很高 高血压正在上升。接受心导管检查的退伍军人中有 28% 出现肾动脉狭窄 65 岁以上人群的风险是其 3 倍以上。尽管如此，心血管和疾病负担仍令人担忧。 肾脏发病率和死亡率，随之而来的是直接医疗费用的增加、生产力和质量的损失 患有高血压的退伍军人的生活。被提名者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- 科学家研究高血压的分子机制。由于 CARP-1 也是 类固醇甲状腺受体的信号传导（Molecular Cell 31: 510-519, 2008），并且知道 已知盐皮质激素受体在肾血管信号传导中发挥重要作用，这是肾血管信号传导的潜在重叠 CARP-1 在该模型中的功能是可以预见的。此外，事实上，抗癌化疗常常 影响患者的心脏功能，被提名者发起了这项合作来研究重叠以及 肾血管模型中血管紧张素-内皮素信号传导的特定的，也许是新颖的方面。虽然这 假设尚未得到检验，提名人迄今为止已在国家期刊上发表了一篇摘要 会议，并担任目前 VA 资助的两项优异申请的联合研究员，重点关注 研究肾血管性高血压的机制。