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.

肥胖和相关的合并症的患病率，包括2型糖尿病和心血管疾病， 公认的是免疫成分 有助于代谢性疾病的病因，尤其是在肥胖驱动的情况下。例如，几乎所有 现有的免疫细胞已显示存在于脂肪组织中（AT）。居民巨噬细胞 被认为有助于通过各种体内稳态功能的AT的发展和正常功能。期间 体重增加，所有免疫小球的数量和表型变化，以使整体环境 它成为促炎性的，促进组织和全身水平的胰岛素抵抗。仓促的实验室 目前，在免疫代谢的这一毛刺领域有2个主要调查领域： 免疫记忆至减肥和体重循环：减肥是减少的理想方法 肥胖的负代谢后果很明显，很难实现持续的体重减轻。回合 体重减轻，然后随后的体重增加导致“体重循环”。有趣的是，在人类中进行了一些研究 证明重量循环会增加患有代谢疾病的风险。 Hasty博士和其他人有 发布的数据显示了体重增加期间AT的抗原反应。她已经提出了假设 重量循环会导致T细胞驱动的继发免疫响应，从而增强了AT的注射 导致局部和全身胰岛素抵抗（IR）。此外，她已经开始研究巨噬细胞是否 在一个称为训练有素的先天免疫的过程中，也“记住”了肥胖环境。这项工作是资助的 获得了VA功绩奖和美国心脏协会的新创新奖。 巨噬细胞的处理：Hasty博士的小组发现了一个新的巨噬细胞人群 对于控制局部铁浓度至关重要，从而有助于脂肪生成并保护 氧化应激。她的实验室最近的进步提供了一个绝佳的机会，可以为居民定义角色 与铁相关的稳态控制中的巨噬细胞。内在免疫代谢，即燃料利用和 细胞的生物能和外部免疫代谢，即影响周围环境的分泌产品 组织环境是影响巨噬细胞如何促进组织的操作特性 稳态。我们将确定铁循环如何影响AT免疫代谢作用的两个臂 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博士在该领域发表了100多个同行评审的手稿，以高影响力期刊在内 糖尿病，自然医学，AM。 J. Physiol。和摩尔。分子。她一直保持着强大的年轻队列 她的小组中的科学家，热衷于培训下一代免疫代谢专家。 Hasty博士 研究与退伍军人高度相关，因为肥胖和代谢疾病的速度甚至更高 比普通平民。这项工作是由Hasty博士进行的，她的团队对我们来说至关重要 了解肥胖加速代谢疾病的免疫介导的机制。