A post-doctoral or graduate student position is available to start as early as January 2017. Experience with tissue stem cell biology, mouse genetics, and cell culture are a plus but are not required. If you are interested, please contact Dr. Horsley for additional information.
There are several possible projects that we could explore:
(1) Defining the role and regenerative mechanisms for mature adipocytes in the skin epidermis
A) Metabolism/Lipid signaling
This exciting project investigates how mature adipocytes contribute to hair cycling and wound healing. Our prior work identifies that adipocytes undergo dynamic lipolysis during hair cycling and in response to injury. This finding has profound implications for understanding tissue regeneration in general, and for chronic wounds in particular. We will employ mouse genetics combined with cell biology, genomics, and biochemical approaches to examine molecular mechanisms of regulation of adipocyte function. We will extend our studies to human skin biology, including implications to skin cancer, through our collaborative efforts with dermatologists and Matthew Rodeheffer at Yale’s Medical School.
This novel project investigates how mature adipocytes contribute to phenotypes associated with aging in the skin including loss of dermal resilience and hair follicles. In Cell Stem Cell, we recently showed that repetitive waxing or with aging, adipose stem cells and mature adipose tissue is lost in skin. We intend to extend these findings to understand how adipocytes contribute to age-related changes in the skin. We will employ mouse genetics combined with cell biology, genomics, and biochemical approaches to examine molecular mechanisms of regulation of adipocyte function.
Systemic sclerosis, an autoimmune disease of unknown origin, is characterized by progressive fibrosis that leads to excessive extracellular matrix protein deposition and increased contractile fibroblasts within the stroma of many organs. To date, there are no effective therapies for the disease. A major outstanding question in the field is how fibrotic cells arise within the stroma of different tissues. Interestingly, mature adipocytes are lost during bleomycin-induced skin fibrosis in mice and human patients with fibrosis (Marangoni et al., 2015; Ohgo et al., 2013). In a project funded by Scleroderma Foundation, we are analyzing whether the loss of lipid storage within skin tissues alters fibroblasts to induce fibrosis using in vitro and in vivo mouse models.
(2) Defining the function and mechanisms of regeneration of adipocytes in the mammary gland
A) Reproductive cycle
During lactation, the mammary gland undergoes dramatic remodeling as epithelial cells generate milk and the underlying stromal cells regress. After lacation ceases, the epithelial cells regress and regenerate the nascent mammary gland structure and the stroma regenerations. In a manuscript in progress, we find that stromal adipocytes are essential for proper epithelial tissue involution. Our future work intends to understand the molecular basis for how adipocytes function in the homeostasis and regeneration of mammary epithelial cells and the stroma.
B) Breast cancer
Obesity and short lactation periods are both associated with triple-negative breast cancer (TNBC; ER-/PR-/HER2-), which has the highest mortality rate and lacks effective therapies (Palmer et al 2014). How obesity and lactation impacts breast tumor development is not well understood. Interestingly, the MG stroma is primarily composed of mature adipocytes and these cells are altered in both obesity and lactation. However, whether stromal adipocytes impact breast tumor formation is not known. We have novel methods to investigate this question using mouse models and in vitro tissue engineering approaches.
(3) Monocytes and their derivatives in epithelial regeneration
Monocytes and their derivatives are excellent therapeutic targets for improving tissue repair. Monocyte-derived cells are required for effective wound repair and can improve human tissue repair. Furthermore, chronic venous leg ulcers or diabetic wounds in mice and humans display alterations in monocyte-derived cells. Since monocytes and their derivatives are found in peripheral sites of the skin at steady state and in sites of inflammation, they can easily be purified, manipulated and reintroduced into patients to aide with wound closure. Yet, recent studies have revealed that monocyte-derived cells are highly heterogeneous and the precise cell type that promotes skin wound healing is not known. We made the intriguing and novel discovery that the recently identified CD301b+ monocyte-derived cells control several aspects of skin wound healing. Therefore, a better understanding of the function of monocyte-derived cells during skin regeneration is expected to advance diagnostic and therapeutic approaches for defective wound healing.
(4) Mechanotransduction via nuclear cytoskeletal interactions
During epidermal keratinocyte differentiation and stratification, the keratinocytes undergo dynamic changes in shape and size. We have shown in collaboration with Eric Dufresne that intercellular adhesions induced during differentiation alter mechanical interactions with the underlying extracellular matrix. Interestingly, this process also induces alterations in the nucleus including changes in shape, size, architecture and transcriptional output. Characteristic alterations in keratinocyte nuclear appearance also manifest in skin diseases such as ichthyosis, cancer and psoriasis. Furthermore, skin dysfunction (alopecia, fibrosis, and epidermal atrophy) is prevalent in diseases associated with mutations in the lamin A/C gene (“laminopathies”). Using keratinocyte culture models and genetic models in mice, we are dissecting how nuclear-cytoskeletal interactions alter epidermal homeostasis and has the potential to impact the treatment of skin defects in laminopathic or other skin diseases that involve alterations to nuclear structure. This work is a collaboration between Dr. Megan King in Yale’s Cell Biology Department.