BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)

• 批准号: 10221206
• 负责人: Alyssa H Hasty
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221206
• 关键词: Adipocytes; Adipose tissue; Affect; American Heart Association; Applications Grants; Appointment; Area; Arteriosclerosis; Award; Basic Science; Bioenergetics; Biology; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Cell Differentiation process; Cells; Committee Members; Data; Development; Diabetes Mellitus; Disease; Environment; Epidemic; Etiology; Faculty; Fibrosis; Foundations; Funding; Glucose Intolerance; Grant; Health; Healthcare; Homeostasis; Hour; Human; IACUC; Immune; Immunologic Memory; Immunology; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; International; Investigation; Iron; Journals; Laboratories; Lead; Link; Lipolysis; Manuscripts; Mediating; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Myelogenous; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Paper; Pathway interactions; Peer Review; Phagocytes; Phenotype; Physiology; Population; Postdoctoral Fellow; Prevalence; Privatization; Process; Property; Protocols documentation; Publications; Publishing; Recording of previous events; Research; Research Personnel; Review Committee; Risk; Role; Scientist; Services; T-Lymphocyte; Thinness; Thrombosis; Time; Tissues; Training; Tumor-infiltrating immune cells; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Veterans; Voting; Weight; Weight Gain; Work; animal care; arm; career; cohort; comorbidity; diabetes risk; early-career faculty; editorial; indexing; innovation; interest; lipid biosynthesis; macrophage; medical schools; meetings; member; mid-career faculty; mitochondrial dysfunction; next generation; novel; obesogenic; professor; response; senior faculty; symposium; tenure track

The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease, has increased dramatically in the past several decades. It is well-established that an immune component contributes to the etiology of metabolic diseases – especially when driven by obesity. For example, nearly all of the immune cells in existence have been shown to reside in adipose tissue (AT). Resident macrophages in AT are thought to contribute to development and proper function of the AT by various homeostatic functions. During weight gain, the numbers and phenotypes of all of the immune cells in AT change such that the overall milieu becomes pro-inflammatory, promoting insulin resistance at the tissue and systemic levels. The Hasty laboratory currently has 2 main areas of investigation in this burgeoning area of immunometabolism: Immunologic memory to weight loss and weight cycling: While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. Bouts of weight loss followed by subsequent weight-gain lead to “weight-cycling”. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. Dr. Hasty and others have published data showing antigenic responses in AT during weight gain. Thus, she has developed the hypothesis that weight-cycling results in a T cell-driven secondary immune response that heightens inflammation in AT, leading to local and systemic insulin resistance (IR). In addition, she has begun to study whether macrophages also “remember” the obesogenic environment in a process called trained innate immunity. This work is funded by her VA Merit Award and by a new Innovation award from the American Heart Association. Macrophage iron handling: Dr. Hasty’s group discovered a novel population of macrophages in AT that are critical for control of local iron concentrations, thereby contributing to adipogenesis and to protection from oxidative stress. Her laboratory’s recent advances offer an excellent opportunity to define a role for resident AT macrophages in iron-related control of AT homeostasis. The intrinsic immunometabolism, i.e. fuel utilization and bioenergetics of the cell, and extrinsic immunometabolism, i.e. secreted products that affect the surrounding tissue environment, are manipulable properties that influence how macrophages contribute to tissue homeostasis. We will determine how iron cycling influences both arms of the immunometabolic role of AT macrophages, thereby influencing systemic insulin action. This work is funded by a new R01. Dr. Hasty has published over 100 peer-reviewed manuscripts in this area in high impact journals including Diabetes, Nature Medicine, Am. J. Physiol. and Mol. Metab. She has always maintained a strong cohort of young scientists within her group, and is keen on training the next generation of immunometabolism experts. Dr. Hasty’s research is highly relevant to Veterans as rates of obesity and metabolic disease are even higher in Veteran’s than in the general civilian population. The work performed by Dr. Hasty and her team are critical for us to better understand immune-mediated mechanisms of obesity-accelerated metabolic disease.

肥胖和相关合并症的患病率，包括 2 型糖尿病和心血管疾病， 众所周知，免疫成分在过去几十年中急剧增加。 导致代谢疾病的病因学——尤其是在肥胖引起的情况下。 现有的免疫细胞已被证明驻留在脂肪组织 (AT) 中的常驻巨噬细胞中。 被认为通过各种稳态功能促进 AT 的发育和正常功能。 体重增加时，AT 中所有免疫细胞的数量和表型都会发生变化，从而导致整体环境 变得促炎，促进组织和全身水平的胰岛素抵抗。 目前在这个新兴的免疫代谢领域有2个主要研究领域： 对减肥和体重循环的免疫记忆：虽然减肥是减少体重的理想方法 肥胖带来的负面代谢后果，显然持续的减肥是很难实现的。 体重减轻随后体重增加会导致“体重循环”。 哈斯蒂博士和其他人证明体重循环会增加患代谢疾病的风险。 发表的数据显示体重增加期间 AT 的抗原反应，因此，她提出了这一假设。 体重循环会导致 T 细胞驱动的二次免疫反应，从而加剧 AT 的炎症， 此外，她还开始研究巨噬细胞是否会导致局部和全身胰岛素抵抗（IR）。 还通过一个称为训练先天免疫的过程“记住”肥胖环境。这项工作得到了资助。 荣获 VA 优异奖和美国心脏协会颁发的新创新奖。 巨噬细胞处理铁：Hasty 博士的研究小组在 AT 中发现了一种新的巨噬细胞群，它们是 对于控制局部铁浓度至关重要，从而有助于脂肪生成并防止 她的实验室的最新进展为定义常驻 AT 的作用提供了绝佳的机会。 巨噬细胞在铁相关的 AT 稳态控制中的作用。 细胞的生物能学和外源性免疫代谢，即影响周围环境的分泌产物 组织环境是可操纵的特性，影响巨噬细胞对组织的贡献 我们将确定铁循环如何影响 AT 的免疫代谢作用。 巨噬细胞，从而影响全身胰岛素作用这项工作由新的 R01 资助。 Hasty 博士在该领域的高影响力期刊上发表了 100 多篇经过同行评审的手稿，包括 糖尿病、自然医学、J. Physiol 和 Mol。 她的团队内有很多科学家，并热衷于培训 Hasty 博士的下一代免疫代谢专家。 研究与退伍军人高度相关，因为退伍军人的肥胖和代谢疾病发生率甚至更高 哈斯蒂博士和她的团队所做的工作对于我们更好地开展工作至关重要。 了解肥胖加速代谢疾病的免疫介导机制。