Investigations in this center are focused on two general aims:
1. The study of epithelial homeostasis and immune regulation at barrier surfaces
2. The regulation of cells that mediate tissue regeneration and repair. Tissue homeostasis is the functional and structural maintenance of the organs of the body. It depends on as yet not fully understood genetic, molecular and cellular processes involved in the repair of structures and functions damaged by the normal functioning of the tissues, disease and/or trauma. The primary barrier between these tissues and the external environment is the sheet of epithelial cells that prevent the invasion of microbes and environmental toxins from the external milieu while preventing the excessive loss of water from the body. As the primary mode of protection from physical and chemical assaults, the epithelium is often damaged and has evolved an amazing capacity to rapidly repair itself. One goal of medicine has been to harness the intrinsic self-renewing ability of damaged tissues to restore their normal structure and function. Stem cells residing in specialized niches of adult tissues are critical actors in homeostatic processes and failures in these regulatory mechanisms incite disease and are an underlying cause of aging. To realize the goal of regenerative medicine requires a detailed understanding of the pivotal role of inflammation in this process. Inflammation is the first response of a tissue to damage and subsequently plays critical roles in bringing various aspects of the healing response to a successful conclusion. Moreover, the trigger for an inflammatory response is exquisitely sensitive to disruptions in the equilibrium of the sheets of epithelial cells that form protective barriers in the body. How epithelial cells relay the information of perturbed homeostasis to initiate an inflammatory response is a crucial early event in the wound-healing program. Likewise, the ability to link the completion of the tissue repair response to the termination of the inflammatory response is an important factor in preventing an immune response from transforming from a protective agent into tissue damaging modality. This occurs because inflammation involves both innate and adaptive immune elements, and the complement and coagulation cascades. When the brakes on the inflammatory response are impaired, prevalent chronic inflammatory diseases such as rheumatoid arthritis, diabetes, atherosclerosis, psoriasis and fibrosis can arise. Consequently, a thorough understanding of the regulation of the inflammatory response would engender new clinical insights into the treatment of many prevalent diseases when this process goes awry. Despite enormous progress in studying the immune system, a holistic understanding of the inflammatory response is not yet in grasp. In addition to their classical role in mounting a counterinsurgency to ward off invaders crossing the breached epithelial barrier, new paradigms on the role of immune derived cytokines on various cell types including stem cells are emerging. Evidence is now accumulating that suggests that inflammatory cells can regulate cell proliferation, differentiation, cell fate specification, migration and invasion and tissue remodeling of multiple cell types. Thus a systemic understanding of how different stem cells are regulated for tissue regeneration and repair and how an inflammatory microenvironment tunes their behavior remains a daunting challenge that needs to be addressed. Filling this gap in our knowledge will overcome a major roadblock that is hindering the development of effective therapies in regenerative medicine. Early experiments in stem cell based therapies have found that the inflammatory microenvironment impacts both the survival of the grafted cells and their ability to differentiate into the cells of interest. Moreover, a comprehensive understanding of the interplay between the inflammatory, proliferative, and remodeling phases of the wound-healing program will likely provide insights into the multitude of diseases with a โwound signatureโ. For instance, there are remarkable parallels between the inflammatory, proliferative and remodeling phases of wound healing program and the characteristics of metastatic tumors. This appreciation for the mechanism by which disruption in the normal wound-healing regimen can prime the tissue to become tumorigenic is an effective manner in which to bridge this center program with our colleagues at IFOM. For instance, IFOM has significant strengths in cell migration, proliferation, and polarity using a gamut of model systems. This center, which operates at the intersection of inflammation and tissue homeostasis would extend upon this base by opening up avenues to understand intercellular interactions within a tumor microenvironment. Current members of the joint center for inflammation and tissue homeostasis are:
Srikala Raghavan, Ph.D. โ role of integrins in regulating epidermal homeostasis; mechanism(s) by which altered tissue homeostasis induces an inflammatory response; role of small RNAs in epithelial stem cells
Shravanti Rampalli-Deshpande, Ph.D. - Cell-fate decisions and maintenance. Epigenetic approaches to restore pluripotency to differentiated cells during development and tissue repair. Colin Jamora, Ph.D. โ regulation of stem cell behavior and fibroblast activation during the wound healing response in the skin; diseases that arise when the wound healing program is perturbed
Ramanuj DasGupta, Ph.D. โ regulation of asymmetric stem cell division by Wnt signaling and its impact on tissue homeostasis
