BLR&D Research Career Scientist Award Application

BLR

基本信息

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
项目类别：
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&apos 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

项目摘要

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肺癌和乳腺癌的总体发病率和死亡率有所增加。由于诊断和治疗方式的进步，特别是在过去十年中有所下降针对包括非小细胞肺癌（NSCLC）在内的多种癌症的靶向治疗。癌症的适应性遗传改变和突变会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，并需要开发新的疗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)。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）继 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，引起 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，以及在此背景下，利用这些知识开发新颖、更安全和有效的抗癌方法。衍生物预计具有临床实用性，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病的患病率很高接受心导管检查的退伍军人中有 28% 发生肾动脉狭窄。 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。科学家研究高血压的分子机制，因为 CARP-1 也是高血压的共同激活剂。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此外，抗癌化疗经常会发挥 CARP-1 的功能。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尽管这可能是肾血管模型中血管紧张素-内皮素信号传导的特定新方面。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。