Mammary Adipocyte Remodeling in Health and Disease

健康和疾病中的乳腺脂肪细胞重塑

基本信息

批准号：
10643697
负责人：
Qiong Annabel Wang
金额：
$ 37.08万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-14 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643697
关键词：
Address Adipocytes Adipose tissue Alveolar Alveolus Apoptosis Back Biology Breast Breast Epithelial Cells Breast Feeding Cell Communication Cell Cycle Cell Proliferation Cells Child Connective Tissue Data Defect Disease Duct (organ) structure Ensure Epithelial Cells Exhibits Fatty acid glycerol esters Fibrosis Functional disorder Health High Fat Diet Hormonal Human Impairment In Vitro Insulin Resistance Knowledge Lactation Mammary Gland Parenchyma Mammary gland Metabolic Diseases Metabolism Milk Modeling Morphogenesis Mothers Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Performance Phenotype Play Pregnancy Process Proliferating Publishing Risk Role Series Structure Testing Time Tissues WNT Signaling Pathway Weaning Woman Work alveolar epithelium cell dedifferentiation design epithelium regeneration feeding in vivo insight lactogenesis mammary mammary epithelium milk production novel novel therapeutic intervention obesity in children obesity treatment paracrine self-renewal

项目摘要

Breastfeeding reduces the mother’s risk of type 2 diabetes and protects the child from obesity, type 2 diabetes, and other metabolic disorders. Unfortunately, mothers with obesity and type 2 diabetes often have insufficient milk production. Lactation by the breast tissue is accomplished through a serious of complicated cellular remodeling, and a “reverse” remodeling post-weaning takes place to return the breast tissue to the non-lactating state (involution). Our understanding of how breast tissue remodels during and post-weaning is limited, which impedes our ability to address lactation complications. The human breast (mammary gland) is comprised of glandular, ductal, connective, and adipose tissue; in the non-lactating mammary gland, the majority of the mass is made up of adipose tissue. My lab recently showed that during lactation, mammary adipocytes undergo a process of dedifferentiation to become adipocyte precursor-like cells; during involution, these dedifferentiated cells can proliferate, and re-differentiate back into adipocytes. Thus, for the first time, we discovered that terminally differentiated mature adipocytes can dedifferentiate, go back to cell cycle, and regain the capacity of self-renewal. Our objective for this proposal is to determine what regulate mammary adipocytes dedifferentiation during lactation, and to define the role of mammary adipocyte dedifferentiation and regeneration during lactation and involution. Our new preliminary data indicate that mammary adipocytes dedifferentiation is due to paracrine stimulation, and Wnt signaling is the top candidate that regulate this process. We also showed that short-term high fat diet feeding leads to incomplete mammary adipocyte dedifferentiation and smaller mammary alveolar structure. Furthermore, inhibiting the regeneration of mammary adipocytes leads to severely delayed mammary gland involution, persistent alveologenesis, periductal fibrosis, and milk retention. We hypothesize that mammary adipocyte dedifferentiation is regulated by paracrine factors from the mammary epithelial cells, especially Wnt signaling, and successful mammary adipocyte dedifferentiation and regeneration are essential for mammary lactation and involution. We will test our hypothesis in three specific aims. In Aim 1, we will determine the mechanisms that regulate adipocyte dedifferentiation during lactation, focusing on Wnt signaling, as well as identifying new paracrine factors. In Aim 2, we will define the role of mammary adipocyte dedifferentiation in mammary alveologenesis and lactogenesis. Specifically, we will determine if incomplete adipocyte dedifferentiation is directly correlated with impaired mammary alveologenesis and lactogenesis. In Aim 3, we will define the role of mammary adipocyte regeneration in mammary gland involution. Our findings will provide fundamental knowledge to the fields of both adipose and mammary gland biology. We will also provide novel insights into lactation and involution complications in women with metabolic disorders. Moreover, the underlying mechanism of mature adipocyte dedifferentiation will bring new strategies for the treatment of obesity.

母乳喂养可以降低母亲患 2 型糖尿病的风险，并保护孩子免受肥胖、2 型糖尿病和其他代谢紊乱的影响。不幸的是，患有肥胖和 2 型糖尿病的母亲通常无法产生足够的乳汁。严重的复杂的细胞重塑，以及断奶后发生的“反向”重塑，使乳腺组织恢复到非哺乳状态（复旧）。我们对断奶期间和断奶后乳腺组织如何重塑的理解。人类乳房（乳腺）由腺体、导管、结缔组织和脂肪组织组成；在非哺乳期乳腺中，大部分肿块由脂肪组成。我的实验室最近表明，在哺乳期间，乳腺脂肪细胞经历去分化过程，成为脂肪细胞前体样细胞；在退化过程中，这些去分化细胞可以增殖，并且因此，我们第一次发现终末分化的成熟脂肪细胞可以去分化，回到细胞周期，并重新获得自我更新的能力。哺乳期间脂肪细胞去分化，并定义哺乳期和复旧期间乳腺脂肪细胞去分化和再生的作用我们的新初步数据表明乳腺脂肪细胞去分化是由于。我们还发现，短期高脂肪饮食喂养会导致乳腺脂肪细胞去分化不完全和乳腺肺泡结构变小，此外，抑制乳腺脂肪细胞的再生会导致严重延迟。我们发现乳腺脂肪细胞去分化受到旁分泌因子的调节。乳腺上皮细胞，特别是 Wnt 信号传导，以及成功的乳腺脂肪细胞去分化和再生对于乳腺泌乳和复旧至关重要。在目标 1 中，我们将确定在哺乳期间调节脂肪细胞去分化的机制。在目标 2 中，我们将定义乳腺脂肪细胞去分化在乳腺中的作用。具体来说，我们将确定不完全的脂肪细胞去分化是否与乳腺肺泡生成和泌乳受损直接相关。在目标 3 中，我们将定义乳腺脂肪细胞再生在乳腺退化中的作用。我们还将对患有代谢紊乱的女性的哺乳和复旧并发症提供新的见解。脂肪细胞去分化将为肥胖治疗带来新策略。