Mechanisms of racial disparity in breast cancer-related lymphedema

项目总结/摘要 这一提议是重要的，因为我们的目标是研究调节细胞内蛋白质的细胞机制。 黑人女性患乳腺癌相关性水肿（BCRL）的风险增加。这很重要 因为BCRL是一种高度病态的疾病，会导致慢性和进行性手臂肿胀。的患者 患有BRCL的患者生活质量下降，需要终生穿着压缩服装进行护理， 出现需要住院治疗的复发性感染。由于乳腺癌的高发病率，BCRL是 这是发达国家最常见的一种水肿，20-35%的女性患有这种疾病， 腋窝淋巴结清扫术（ALND）。 为了确定BCRL的危险因素，我们的研究小组前瞻性地随访了276名有手臂的妇女， 在ALND之前和之后2年进行测量。我们发现黑人女性的风险最高， 即使在调整混杂变量后，BCRL也是如此。在我们的研究中，黑人增加了BCRL的风险， 与白色人种相比，发育提高>3.6倍。这些发现得到了其他两个出版物的支持。 研究报告了因乳腺癌接受ALND的黑人妇女发生BCRL的风险增加。 因此，虽然有强有力的证据表明黑人妇女患BCRL的风险显著增加， 调节这种风险的细胞机制仍然未知。我们知识上的这一差距是重要的， 这是开发预防或治疗该患者人群水肿的新疗法的主要障碍。在 此外，了解黑人种族如何增加BCRL的风险可能有助于阐明 调节这种疾病的病理生理学。根据先前的研究和我们的初步研究， 我们的中心假设是，由于基线，黑人妇女患BCRL的风险增加， 增加炎症和纤维化的倾向。我们建议使用两个具体目标来检验这一假设。 在目标1中，我们将分析种族差异如何调节淋巴损伤后的炎症反应。 这一假设是基于以下发现，即水肿的病理生理学与慢性炎症有关。 炎症和T辅助细胞2（Th 2）偏向的免疫应答的发展。黑人患者有 在其他病理环境中的炎症倾向，表明这些差异也可能 会增加BCRL的风险。在目标2中，我们将检验黑人妇女 对水肿的纤维化反应增加。这一假设是基于纤维化的观察， 是水肿的关键病理特征，并在调节淋巴功能中起主要作用。黑色 个体在各种病理环境中具有增加的纤维化的可能性 皮肤病

PROJECT SUMMARY/ABSTRACT This proposal is significant because we aim to study the cellular mechanisms that regulate the increased risk of breast cancer-related lymphedema (BCRL) development in Black women. This is important because BCRL is a highly morbid disease that causes chronic and progressive arm swelling. Patients who develop BRCL have diminished quality of life, require life-long care with compression garments, and can develop recurrent infections that require hospitalization. Due to the high prevalence of breast cancer, BCRL is the most common form of lymphedema in developed countries, afflicting 20–35% of women who undergo axillary lymph node dissection (ALND). To identify risk factors for BCRL, our group has prospectively followed 276 women with arm measurements before and after ALND for 2 years. We have found that Black women have the highest risk of BCRL even after adjusting for confounding variables. In our study, Black race increased the risk of BCRL development by >3.6 fold compared with White race. These findings are supported by two other published studies reporting increased risk of BCRL development in Black women who undergo ALND for breast cancer. Thus, while there is strong evidence that Black women have a significantly increased risk of developing BCRL, the cellular mechanisms that regulate this risk remain unknown. This gap in our knowledge is important and a major barrier to developing novel therapies that prevent or treat lymphedema in this patient population. In addition, understanding how Black race increases the risk of BCRL may shed light on the mechanisms that regulate the pathophysiology of this disease in general. Based on prior research and our preliminary studies, our central hypothesis is that Black women have an increased risk of developing BCRL due to a baseline increased propensity for inflammation and fibrosis. We propose to test this hypothesis using two Specific Aims. In Aim 1, we will analyze how racial disparities modulate inflammatory responses following lymphatic injury. This hypothesis is based on the finding that the pathophysiology of lymphedema is linked to chronic inflammation and development of T-helper 2 (Th2)-biased immune responses. Black patients have a propensity for inflammation in other pathological settings, suggesting that these differences may also contribute to an increased risk for developing BCRL. In Aim 2, we will test the hypothesis that Black women have an increased fibrotic response to lymphedema. This hypothesis is based on the observation that fibrosis is a key pathological feature of lymphedema and plays a major role in regulating lymphatic function. Black individuals have an increased potential for fibrosis in a variety of pathological settings including inflammatory skin disorders.