BLR&D Research Career Scientist Award Application

炎症是身体试图自我保护，以消除有害的刺激和开始愈合过程。 慢性炎症最终会导致几种疾病和病症，包括癌症、类风湿性关节炎、 关节炎、动脉粥样硬化，并在心脏病中发挥作用。被提名人研究的首要目标 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，肺结核和肺结核导致的新病例和死亡率最高， 女性患乳腺癌，而前列腺癌和肺癌在新病例中所占比例最高， 与男性相关的死亡率肺癌和乳腺癌的总体发病率和死亡率 在过去十年中，由于诊断和治疗方式的进步， 靶向治疗包括非小细胞肺癌（NSCLC）在内的多种癌症。然而，在这方面， 癌症中的适应性遗传改变和突变导致临床治疗失败和复发 这常常导致出现耐药性、难以治疗疾病，并保证开发新的治疗方法 克服耐药性和改善治疗结果的战略。 通过利用功能性基因敲除方法，被提名者鉴定了一种新的凋亡诱导蛋白 称为CARP-1/CCAR 1（J.Biol.Chem.278：33422-33435，2003）。CARP-1调控细胞凋亡信号 由多种化疗药物诱导，如阿霉素、依托泊苷和吉非替尼（由提名人在 Oncotarget6（9）：6499-510，2015）。在CARP-1发现后，被提名人进行了化学生物学研究， 鉴定新的小分子CARP-1功能模拟物（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，包括治疗抗性三阴性 乳腺癌（TNBC）和非小细胞肺癌（NSCLC）部分通过与CARP-1结合， CARP-1和细胞凋亡水平升高（Oncotarget，2016，出版中）。被提名人的长期目标是 阐明耐药性TNBC和NSCLC细胞模型中的治疗耐药性的分子机制，以及 利用这些知识来开发新的，更安全和有效的抗癌模式。在这种情况下，外交部长或其 预期衍生物具有临床实用性，并可提供开发未来策略的新手段 有效治疗TNBC，NSCLC和VA医疗保健系统内外的其他癌症。 高血压在美国是一个主要的健康问题，和动脉粥样硬化性肾血管病变的患病率 高血压正在上升。28%接受心导管插入术的退伍军人发生肾动脉狭窄， 65岁以上的人患病风险超过3倍。尽管如此，心血管疾病的负担令人担忧， 肾脏发病率和死亡率，伴随着直接医疗费用的增加，生产力和质量的损失， 生活在我们的退伍军人与高血压。被提名者与底特律VA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也是一种共激活剂， 通过类固醇-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起重要作用， 设想了CARP-1在该模型中的功能。此外，事实上，抗癌化疗往往 影响患者的心脏功能，被提名人发起了这项合作，研究重叠以及 具体的，也许是新的方面的血管紧张素-内皮素信号在肾血管模型。虽然这 假设还有待检验，被提名者迄今为止在一个国家的摘要出版物作出了贡献。 会议，并担任目前两个VA资助的Merit应用程序的共同研究者，重点是 研究肾血管性高血压的机制。

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.