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：
10364742
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/10364742
关键词：
Address Adipocytes Adipose tissue Alveolar Alveolus Apoptosis Back Biology Breast Breast Epithelial Cells Breast Feeding Cell Cycle 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 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 design epithelium regeneration feeding in vivo insight lactogenesis mammary mammary epithelium milk production novel obesity in children obesity treatment paracrine self-renewal treatment strategy

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.

母乳喂养降低了母亲患2型糖尿病的风险，并保护孩子免受肥胖症，2型糖尿病和其他代谢疾病的侵害。不幸的是，患有肥胖症和2型糖尿病的母亲通常牛奶产量不足。通过严重的复杂的细胞重塑来完成乳房组织的泌乳，并进行了“反向”重塑后断奶后，将乳房组织恢复到非乳腺状态（相关性）。我们对乳房组织在断奶过程中的改造有限的理解是有限的，这阻碍了我们解决泌乳并发症的能力。人乳腺（乳腺）由腺体，导管，连接和脂肪组织组成。在非乳腺乳腺中，大部分质量是由脂肪组织组成的。我的实验室最近表明，在哺乳期，乳腺脂肪细胞经历了去分化的过程，成为脂肪细胞前体样细胞。在互动期间，这些去分化的细胞可以增殖，并重新分化回脂肪细胞。这是第一次，我们发现末端分化的成熟脂肪细胞可以去分化，回到细胞周期，并恢复自我更新的能力。我们对该提案的目标是确定泌乳过程中哪些调节乳腺脂肪细胞的去分化，并确定乳腺脂肪细胞去分化和再生在泌乳和参与过程中的作用。我们的新初步数据表明，乳腺脂肪细胞的去分化是由于旁细胞烯刺激引起的，而Wnt信号传导是调节这一过程的最高候选者。我们还表明，短期高脂肪饮食喂养会导致不完整的乳腺脂肪细胞去分化和较小的乳腺结构。此外，抑制乳腺脂肪细胞的再生会导致严重延迟的乳腺相关性，持续性肺泡术，纤维化纤维化和牛奶保留。我们假设乳腺脂肪细胞去分化受到乳腺上皮细胞的旁分泌因子的调节，尤其是Wnt信号传导，成功的乳腺脂肪细胞去分化和再生对于乳腺泌乳和参与至关重要。我们将以三个特定目标来检验我们的假设。在AIM 1中，我们将确定调节泌乳过程中脂肪细胞去分化的机制，重点关注Wnt信号传导，并确定新的旁分泌因子。在AIM 2中，我们将定义乳腺脂肪细胞去分化在乳腺肺泡术和泌乳发生中的作用。具体而言，我们将确定不完全的脂肪细胞去分化是否与受损的乳腺肺单术和乳酸发生直接相关。在AIM 3中，我们将定义乳腺脂肪细胞再生在乳腺相关性中的作用。我们的发现将为脂肪和乳腺生物学领域提供基本知识。我们还将为患有代谢疾病的女性的泌乳和相关并发症提供新的见解。此外，成熟的脂肪细胞去分化的基本机制将带来肥胖治疗的新策略。