Grants We Funded

Abstract
This proposal is significant because we aim to develop novel treatments for lymphedema, a common and morbid complication of cancer treatment that results in chronic swelling, recurrent infections, and deadly tumors. Recent clinical studies have reported decreased swelling and symptomatic relief after lymph node transfer (LNT) to the affected limb. To study the mechanisms of this process, we have developed a mouse model of LNT and have shown that the lymphatic vessels of the lymph node spontaneously reconnect with the lymphatics of the recipient site thereby restoring lymphatic circulation. However, although these results are promising, it remains unclear if immunologic function is restored after LNT. This is important because understanding the mechanisms by which LNT regulates immune function and microenvironmental changes is a necessary step for improving these outcomes.
Our approach is innovative because we have developed an inducible mouse model of lymphedema in which tissue lymphatics can be selectively ablated using diphtheria toxin. This enables us to study immune function after LNT in a clinically relevant model and test the central hypothesis that lymphatic regeneration after LNT restores immune function and promotes resolution of tumorigenic microenvironmental changes.
Aim 1: Determine how LNT restores immune function. This aim will test the hypothesis that innate and adaptive immune function is restored after LNT. The rationale for these studies is based on the fact that patients who have undergone lymph node dissection or suffer from lymphedema have impaired antibody response and are at increased risk for infections.
Aim 2: Determine how LNT regulates lymphatic injury induced microenvironmental changes. This aim will test the hypothesis that LNT reverses microenvironmental changes after lymphatic injury. The rationale for these studies is based on our recent study demonstrating that lymphedema, both clinically and in mouse models, results in inflammation, accumulation of T-regulatory cells and upregulation of IL6 expression.
At the conclusion of the proposed study we expect to understand the mechanisms that regulate impaired immune function and promote environmental changes after lymphatic injury and how these responses are altered by LNT. These studies are therefore not only important to patients with lymphedema but will also increase our general understanding of how the lymphatic system can regulate its microenvironment.

Biography
Gabriela Garcia Nores was raised Lima, Peru and graduated 4th of her class with an MD from the Universidad de San Martin de Porres, Facultad de Medicina Humana. During her training in Peru, she was introduced to lymphedema as a consequence not only of surgery but also of infection. After validating her title in the US, she completed three years of general surgery training at NYU Medical Center. She then began a prestigious research fellowship at Memorial Sloan Kettering Cancer Center under the guidance of Dr. Babak Mehrara, MD, FACS. Dr. Garcia Nores has focused her research efforts on improving the scientific understanding of immunity after lymph node transfer and the molecular mechanisms leading to lymphedema and pharmacological targets to improve its treatment.