Showing papers by "Eric G. Neilson published in 2003"

Epithelial-mesenchymal transition and its implications for fibrosis.

Abstract: Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.

Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

Abstract: Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport's syndrome and acquired Goodpasture's syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.

The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis.

Abstract: When carcinoma cells metastasize, they change their phenotype to enhance motility. Cells making this switch selectively express S100A4, a p53-associated, calcium-binding protein known in the fibroblast literature as fibroblast-specific protein-1 (FSP1). FSP1 normally acts as a conversion signal for the local formation of tissue fibroblasts by epithelial-mesenchymal transition. We describe here a novel connection between the process of fibroblast development and the acquisition of a metastatic phenotype in genetically engineered mice with mammary carcinoma. More frequent lung metastases were observed in naive recipients given purified populations of green fluorescent protein (GFP)(+) tumor cells harvested from PyV-mT x FSP1(+/+.GFP) F1 mice compared with GFP(-) tumor cells (P < or = 0.01), where GFP expression is under the control of the FSP1 promoter. The expression of GFP in these metastases reversibly attenuates with the establishment of secondary tumor nodules. Reduced numbers of metastases were also observed in PyV-mT x FSP1(GFP/GFP) F1 mice carrying null alleles for FSP1 (P < or = 0.04) and in PyV-mT x FSP1.Delta TK(+) F1 mice rescued with nucleoside analogues while expressing thymidine kinase under the control of the FSP1 promoter (P < or = 0.01). We propose that epithelial-mesenchymal transition associated with the expression of FSP1 in tumor cells has a functional role in determining the latency of tumor dispersion and may be a convenient therapeutic target for controlling a key initiating event in metastatic progression.

New insights into mechanisms of fibrosis in immune renal injury.

Abstract: . Renal fibrosis is the final common pathway for many kidney lesions that lead to chronic progressive organ failure. The tubulointerstitial space occupies up to 90% of kidney volume, indicating that pathological changes in that space can not be without functional significance. By analogy to wound healing, renal fibrogenesis can be divided arbitrarily into three phases: induction, inflammatory, and post-inflammatory phases. The latter phase is of particular importance, since its length often exceeds what would be required for healing. The induction phase is characterized by the infiltration of the tubulointerstitial space by mononuclear inflammatory cells. This influx is mediated by proinflammatory cytokines and chemokines often secreted by activated tubular epithelial cells. Subsequently, these infiltrating mononuclear cells stimulate a heterogeneous group of resident fibroblasts and tubular epithelial cells to undergo phenotypic conversion into activated fibroblasts that secrete abundant extracellular matrix. Tubular epithelial cells contribute to this process through epithelial-mesenchymal transition. During the inflammatory phase these activated fibroblasts are stimulated to produce collagenous matrix mainly by cytokines, such as TGF-β1, EGF, ET-1, and FGF-2, which are secreted by inflammatory and injured somatic cells. Occasionally however, when inflammation subsides, the matrix synthesis in the post-inflammatory phase of renal fibrogenesis continues and may be more dependent on autocrine stimulation from resident renal cells such as remaining tubular epithelium. Eventually, the collagenous matrix of fibrogenesis destroys blood supply and the perimeter of viability for fibroblasts regresses to the point where scars become acellular.

Effects of performance-based compensation and faculty track on the clinical activity, research portfolio, and teaching mission of a large academic department of medicine.

Abstract: PURPOSE Academic departments of medicine must compete effectively for extramural research support and access to patients while preserving their teaching mission. There is not much literature describing plausible mechanisms for ensuring success. The authors describe the design, implementation, and testing of a performance-based compensation plan in a department of medicine that is closely linked to the faculty appointment track. METHOD Over a three-year period, the changes this plan effected in research portfolio, clinical enterprise, and faculty satisfaction as well as the teaching perceptions of students and housestaff were measured. RESULTS The compound annual growth rate (CAGR) for clinical work grew 40% faster after plan implementation. Federal funding increased at a CAGR that was 170% greater than before. The department halved its award rankings at the National Institutes of Health and faculty satisfaction improved compared with the former method of compensation. Faculty who better understood the plan were more satisfied with the conversion. High measures of teaching quality were maintained by faculty with no apparent change in satisfaction among students or housestaff. CONCLUSIONS This performance-based compensation plan with its emphasis on the objectives of career orientation and faculty track assignment strengthened the opportunity to grow both clinical productivity and the funded research portfolio.

The role of medical school admissions committees in the decline of physician-scientists

Abstract: Numerous articles written over the last few years have drawn attention to the disappearance of young physician-scientists (1–5). There are nearly 25% fewer physician-scientists on medical school faculties today than two decades ago (6) and now we know some of the reasons. The heavy accumulation of debt through many years of research training is one explanation (7). So is the difficulty of providing a useful research experience in the modern training curriculum (8–10), or reaching trainees who have no real understanding of what it means to be a physician-scientist before their career choices are made (3, 11). Some students attend medical schools that offer little investigative opportunity (3, 12, 13), and of course there are questions about earning a living from academic life. While these reasons partly explain the problem, I would add one more. Medical schools no longer matriculate sufficient numbers of students who are deeply interested in science.