Abstract

Desmosomes are specialized plasma membrane domains that function as cell-cell junctions as well as attachment sites for the intermediate filament network. Impaired desmosome function can lead to cell- and tissue-fragility disorders, particularly in stratified epithelia. We have analyzed the function of desmocollin 1 (dsc1), a desmosomal transmembrane glycoprotein that is expressed in terminally differentiating keratinocytes. Dsc1 is synthesized in two forms (a- and b-form) that differ only with respect to their COOH-terminal (cytoplasmic) amino acid sequences. In vitro experiments suggested that dsc1a might be crucial for the assembly of the desmosomal plaque, a structure that connects the desmosome to intermediate filaments. The function of dsc1b is not known. Our study was designed to evaluate the contributions of the dsc1 splice variants to normal epidermal development and function. We generated mice that synthesize a truncated dsc1 receptor which contains the extracellular and cytoplasmic domains that are common to both dsc1a and dsc1b. The truncated receptor, however, contains neither the dsc1a- nor the dsc1b-specific COOH-terminal cytoplasmic domains. Mutant mice developed normally. However, they showed a single biochemical abnormality: dsc2 mRNA expression was dramatically increased whereas dsc2 protein synthesis remained essentially normal. Based on these results we concluded that: 1. The dsc1a- and dsc1b-specific domains are not essential for normal tissue development and function. 2. Regulatory mechanisms must exist that tightly control the synthesis of desmocollins in vivo. (Presented at the 1317th Meeting, May 27, 2003.)

The medical school curriculum directly influences whether the students will be motivated or not. Several components seem to be important in making the curriculum exciting for the students: participatory and hands-on curriculum, providing clear goals and maps throughout the learning process, avoiding "big jumps" during the curriculum, and internal and external evaluation systems for further improvement. In US medical schools, even if not perfect, serious interests and efforts are seen in all of the above. For instance, in order to make the learning process active and participatory, PBL (problem-based learning) is becoming more and more common in the basic science courses. Hands-on curriculum translates into early clinical exposure and clinical clerkship where students take an active role in patient care instead of being a "guest" on the wards. The existence of the syllabus provides clear goals and guidance for the students taking the course. In order to avoid big jumps during the training, clinical ability such as history taking, physical exam skills and clinical thinking process is gradually introduced and steadily advanced throughout the whole curriculum. In order to augment training in acute care settings, computer-based interactive human simulators are used at some institutions including the University of Pittsburgh. Evaluation of the instructor and the curriculum by the student is standard and the teaching is equally valued as research at US Medical Schools. In addition to internal evaluation, there is also an accreditation system in the US by the ACGME (Accreditation Council on Graduate Medical Education) where the third party objectively evaluates the curriculum periodically. (Presented at the 1318th Meeting, June 2, 2003.)

Leptin is an adipocyte-derived circulating satiety factor that is involved in the regulation of food intake and body weight. We created transgenic skinny mice with hepatic overexpression of leptin and demonstrated that they exhibit increased glucose metabolism and insulin sensitivity. This has led us to speculate the potential usefulness of leptin as an antidiabetic agent. We have found that a subthreshold of dose of insulin in conjunction with leptin is sufficient to normalize the hyperglycemia in STZ-induced diabetic mice and suggested that leptin may be an adjunct to insulin therapy in insulin-dependent diabetes. We also found that transgenic overexpression of leptin can delay the onset of insulin resistance and diabetes in KKA^y mice at younger ages, and suggested that leptin alone is effective in non-insulin-dependent diabetes, without obesity. However, chronic hyperleptinemia did not prevent the progression of diabetes in KKA^y mice at older ages, suggesting leptin alone may not be effective in obesityrelated diabetes. In this case, leptin may be used as an adjunct to caloric restriction aimed at achieving good glycemic control, because transgenic overexpression of leptin could accelerate the recovery from diabetes in calorically-restricted KKA^y mice. We also found that chronic hyperleptinemia can rescue the insulin resistance and diabetes in a mouse model of lipoatrophic diabetes, demonstrating that leptin alone is effective in lipoatrophic diabetes. Thus, leptin therapy for both congenital and acquired forms of lipoatrophic diabetes is currently ongoing worldwide. Collectively, our data suggest the therapeutic potential of leptin in various types of diabetes. (Presented at the 1321st Meeting, July 8, 2003.)

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