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General Surgery
CIMIT
Principal Investigator:
David W. Rattner, M.D.
Group Members:
John Guttag, Ph.D.
Nicholas Stylopoulos, M.D.
James Ellsmere, M.D. The Center for Innovative Minimally Invasive Therapy (CIMIT) has multiple programs crossing the surgical disciplines. Within General Surgery, the primary focus areas are computer-assisted surgery and designing the operating environment for the future.
Computer Assisted Surgery:
In conjunction with the Harvard Center for Minimally Invasive Surgery and the Surgical Planning Laboratory, we have developed methods to co-register laparoscopic ultrasound with preoperatively obtained imaging data. This work facilitates use of laparoscopic ultrasound. The future of minimally invasive surgery is likely to caitalize on this type of image guidance. Ongoing work is being performed to take this work from the animal lab to the operating room.
OR of the Future:
In conjunction with the School of Computer Science and Electrical Engineering at MIT, we are exploring the use of new information technology to create a local area network which is wireless and will incorporate remote sensing devices. Additional projects related to the operating room of the future are outcomes data evaluation on patient processes and medical errors, the use of data mining algorithms to identify potentially risky situations, and the use of radiofrequency identification tagging for both instruments and personnel.
Outcomes Research:
In conjunction with the MGH Data group, we have recently concluded large population based studies on the natural history of both inguinal hernia and paraesophageal hernia. Future efforts are ongoing to extract data from the National Inpatient Sample (NIS) as well as other recently available databases and look at problems such as optimal treatment for liver metastases and Barrett’s esophagus.
Surgical Simulation:
In conjunction with the CIMIT Simulation Group, we have developed methodology to track a surgeon’s movements in performing complex procedures. This simulation tool is being validated and will provide feedback to surgeons as they learn specific laparoscopic tasks. This level of detailed feedback is unique, far surpassing standard training boxes, and ultimately will be used to design the haptic interface of surgical simulators for the future.
Laboratory of Gastrointestinal Epithelial Biology
Principal Investigator:
Richard A. Hodin, M.D.
Group Members:
Madhu Malo, MD,PhD
Brian Hinnebusch MD
Mario Abedrapo MD
Wengying Zhang MD
Joseph Welles-Henderson BA
Aleem Siddique MD
The major focus of the laboratory is to unravel the molecular mechanisms that underlie the processes of growth and differentiation within intestinal epithelia. The various projects ongoing in the lab relate to understanding the differentiation process in the contexts of (1) normal development, (2) homeostasis within the adult, and (3) pathological conditions such as cancer and inflammatory bowel disease.
(1) Gut Development: The mammalian small intestine undergoes a very precise and complex series of morphological and biochemical changes during pre- and post-natal development. Among the most critical factors involved in this process is thyroid hormone. Animals that are hypo-thyroid or lack thyroid hormone receptors exhibit profound abnormalities within the gut mucosa. We are investigating the molecular mechanisms by which thyroid hormone exerts its effects upon intestinal epithelial growth and differentiation.
(2) Gut Homeostasis: The gut epithelium is a dynamic structure that undergoes a continuous cycle of self-renewal, with pluripotent stem cells located in the crypts giving rise to fully-differentiated villus cells. We are studying the differentiation process of the enterocyte, the cell that comprises 95% of all villus cells and is responsible for the nutrient digestion and absorption that is critical to life. The enterocyte marker gene, intestinal alkaline phosphatase (IAP) is being used as a tool to identify and characterize transcription factors that mediate the differentiation process. Among the mechanisms which underlie gut differentiation is a specific alteration in chromatin structure. We have therefore employed novel techniques to examine the role that histone proteins play in enterocyte growth and differentiation.
(3) Gut Pathology: Unfortunately, the normal differentiation process goes awry under a variety of conditions, many of which are seen in surgical patients. Perhaps most notable is the gut mucosal failure that occurs with starvation, ischemia, or inflammatory conditions. We have identified specific alterations in the phenotype of the enterocyte that appears to be a reliable marker for this gut mucosal failure and have ongoing studies that are geared toward an elucidation of this abnormal phentoype and the molecular events that cause it. In addition, it is quite clear that cancer of the GI tract (i.e., colon cancer) represents a failure in the normal growth and differentiation cues within the epithelium. We are using a variety of human colon cancer-derived cell lines as well as in vivo models of colon carcinogenesis to unravel the transcriptional events that govern the neoplastic process. We have been particularly interested in the beneficial effects of fiber-derived short-chain fatty acids in blocking the development and growth of colon tumors.
Laboratory Funding
NIH R01 DK47186 "Molecular mechanisms of intestinal atrophy/hyperplasia" 8/1/94-3/31/05
The major goals of this project are to examine the molecular mechanisms that underlie the alterations in gut epithelia that accompany intestinal atrophy and hyperplasia.
NIH R01 DK50623 "Thyroid hormone and the gut" 9/1/96-8/31/06
The major goals of this project are to elucidate the molecular mechanisms by which thyroid hormone exerts its effect upon gastrointestinal mucosal structure and function.
NIH/T32 "Research training in alimentary tract surgery" 7/1/97-6/30/02
The goal of this grant is to provide excellent training for young surgeons interested in a career as a surgeon-scientist in the field of gastrointestinal surgery.
Selected Publications
1. Lazar MA, Hodin RA, Darling DS, Chin WW. Identification of a rat c-erbAa-related protein which binds deoxyribonucleic acid but does not bind thyroid hormone. Mol. Endocrinol. 1988; 2:893-901.
2. Lazar MA, Hodin RA, Darling DS, Chin WW. A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbAa transcriptional unit. Mol. and Cell Bio., 1989; 9:1128-36.
3. Hodin RA, Lazar MA, Chin WW. The Pituitary-specific form of rat c-erbA is a biologically active thyroid hormone receptor. Curr. Surg. 1989;46:298-301.
4. Lazar MA, Hodin RA, Chin WW. Human Carboxyl-terminal variant of alpha-type c-erbA inhibits transactivation by thyroid hormone receptors without binding thyroid hormone. Proc. Natl. Acad. Sci USA 1989;86:7771-4.
5. Koenig RJ, Lazar MA, Hodin RA, Brent GA, Larsen PR, Chin WW, Moore DD. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature 1989; 337:659-661.
6. Hodin RA, Lazar MA, Wintman B, Darling DS, Koenig RJ, Larsen PR, Moore DD, Chin WW. Identification of a thyroid hormone receptor that is pituitary-specific. Science 1989; 244:76-79.
7. Hodin RA, Lazar MA, Chin WW. Differential and tissue-specific regulation of the multiple rat c-erbA mRNA species by thyroid hormone. J. Clinic Invest. 1990; 85:101-105.
8. Lazar MA, Hodin RA, Cardona G, Chin WW. Gene expression from the c-erbA alpha/REV-ERBA alpha genomic locus. Potential regulation of alternative splicing by opposite strand transcription. J. Biol. Chem. 1990;265: 12859-63.
9. Hodin RA, Chamberlain SM, Upton M. Thyroid hormone differentially regulates rat small intestinal brush-border enzyme gene expression. Gastroenterology 1992;103:1529-1536
10. Hupart KH, Hodin RA, Lazar MA, Shapiro LE, Chin WW, Surks MI. c-erbA mRNA correlates with T3 receptor levels in liver and pituitary of tumor rats.Thyroid 1993;3:55-58.
11. Hodin RA, Meng S. Regulation of intestinal alkaline phosphatase gene expression in HT-29 cells. Surgical Forum, Vol. XLIV 1993; 128-130.
12. Hodin RA, Graham JR, Meng S, Upton MP. Temporal pattern of rat small intestinal gene expression with refeeding. Am. J. Physiol. 1994; 266:G83-G89.
13. Hodin RA, Meng S, Nguyen D. Immediate-early gene expression in EGF-stimulated intestinal epithelial cells. J. Sur. Res. 1994; 56:500-504.
14. Hodin RA, Meng S, Shei A. Bombesin maintains enterocyte phenotype in fasted rats. Surgery 1994; 116:426-431.
15. Hodin RA, Meng S, Chamberlain SM. Thyroid hormone responsiveness is developmentally regulated in the rat small intestine: A possible role for the µ-2 receptor variant. Endocrinology 1994; 135:564-568.
16. Hodin RA, Meng S, Shei A. Gastrin regulates lactase gene expression in the intact rat. Surgical Forum, 1994;178-180.
17. Hodin RA, Chamberlain SM, Meng, S. Pattern of rat intestinal brush-border enzyme gene expression changes with epithelial growth state. Am. J. Physiol. 1995; 269:C385-C391.
18. Hodin RA, Meng S, Shei A. Differential cloning of novel intestine-specific genes whose expression is altered under conditions of villus atrophy. J. Sur. Res. 1995; 59:115-120.
19. Hodin RA, Saldinger P, Meng S. Small bowel adaptation: counter-regulatory effects of EGF and somatostatin on the program of early gene expression. Surgery 1995;118:206-211.
20. Hodin RA, Shei A, Morin M, Meng S. Thyroid hormone and the gut: Selective transcriptional activation of a villus-enterocyte marker. Surgery 1996; 120:138-143.
21. Hodin RA, Meng S, Archer S, Tang R. Cellular growth state differentially regulates enterocyte gene expression in butyrate treated HT-29 cells. Cell Growth & Differentiation 1996;7:647-653.
22. Meng S, Matthews JB, Hodin RA. Downregulation of Na-K-Cl cotransporter gene expression during enterocyte differentiation along the crypt-villus axis. Surgical Forum 1996; 47:178-180.
23. Hodin RA, Meng S, Shei A. Transcriptional activation of the human villin gene during enterocyte differentiation. J. Gastrointest Surg, 1997;1:433-438.
24. Unno N, Wang H, Menconi MJ, Tytgat SHAJ, Larkin V, Smith M, Morin M, Hodin RA, Fink M. Inhibition of inducible nitric oxide synthase ameliorates lipopolysaccharide-induced gut mucosal barrier dysfunction in rats. Gastroenterology, 1997; 113:1246-1257.
25. Archer S, Meng S, Shei A, Hodin RA. Importance of histone hyperacetylation and the p21 gene in butyrate-induced growth arrest of colon carcinoma cells. Surgical Forum, 1997; 833-836.
26. Chavez AM, Morin MJ, Unno N, Fink MP, Hodin RA. Cellular responsiveness to interferon-gamma is acquired during enterocyte differentiation in vitro: effects on inducible nitric oxide synthase gene expression. Surgical Forum, 1997; 219-221.
27. Morin M, Unno N, Hodin RA, Fink MP. Differential expression of inducible nitric oxide synthase messenger RNA along the longitudinal and crypt-villus axes of the intestine in endotoxemic rats. Critical Care Medicine, 1998; 26:1258-1264.
28. Matthews JB, Hassan I, Meng S, Archer S, Hrnjez BJ, Hodin RA. Na-K-2Cl cotransporter gene expression and function during enterocyte differentiation: modulation of C1- secretory capacity by butyrate. J. Clinic. Invest., 1998; 101:2072-2079.
29. Archer S, Meng S, Grable P, Hodin RA. Butyrate inhibits colon carcinoma cell growth via two distinct pathways. Surgery, 1998; 95:6791-6796.
30. Archer SY, Meng S, Shei A, Hodin RA. p21WAF1 is required for butyrate mediated growth inhibition of human colon cancer cells. Proc Nat Acad Sci, 1998; 95:6791-6796.
31. Unno N, Nakamura S, Baba S, Hodin RA, Fink MP. Lipopolysaccharide-induced inducible nitric oxide synthase (iNOS) gene expression is down-regulated in rats rendered tolerant to endotoxin, possibly as a result of enhanced glucocorticoid release. Surgical Forum 1998;10-11.
32. Meng S, Archer S, Hodin RA. Thyroid hormone and gut differentiation: molecular mechanisms of action. Surgical Forum, 1998; 126-127.
33. Kim J, Shei A, Meng S, Hodin RA. A novel Sp1-related cis-element involved in intestinal alkaline phosphatase gene transcription. Am. J. Physiol. 1999;276:G800-G807.
34. Chavez AM, Morin MJ, Unno N, Fink MP, Hodin RA. Acquired interferon-g-responsiveness during enterocyte differentiation: effects on iNOS gene expression. Gut 1999;44:659-665.
35. Unno N, Hodin RA, Fink MP. Acidic conditions exacerbate interferon-g-induced intestinal epithelial hyperpermeability: Role of peroxynitrous acid. Crit Care Med 1999;27:1429-36.
36. Meng S, Wu J, Archer S, Hodin RA. Short chain fatty acids and thyroid hormone interact in regulating enterocyte gene transcription. Surgery 1999;126:293-298.
37. Farokhzad OC, Vivek Sagar GD, Mun, EC, Sicklick JK, Lotz M, Smith JA, Song JC, O’Brien TC, Sharma CP, Kinane TB, Hodin RA, and Matthews, JB. Protein kinase C activation downregulates the expression and function of the basolateral Na+/K+/2CL- cotransporter. J. Cell Physiol. 1999;181:489-498.
38. Chavez AM, Menconi MJ, Hodin RA, Fink MP. Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. Crit Care Med, 1999;27:2246-2251.
39. Meng S, Archer SY, Hinnebusch BF, Hodin RA. Short chain fatty acids and colon cancer cell phenotype: the link to chromatin structure. Surgical Forum 2000; 70-72
40. Meng S, Badrinarain J, Sibley E, Fang R, Hodin RA. Thyroid hormone and the D-type cyclins interact in regulating enterocyte gene transcription. J Gastro Surg 2001; 5:49-55
41. Wu JT, Archer SY, Hinnebusch B, Meng S, Hodin RA. Transient vs. prolonged histone hyperacetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Am J Physiol 2001;280:G482-G490
42. Archer SY, Johnson JJ, Kim HJ, Hodin RA. p21 gene regulation during enterocyte differentiation. J. Sur. Res. 2001; 98: 4-8.
43. Hinnebusch BF, Kim J, Meng S, Badrinarain J, Hodin RA. Transcriptional regulation of the enterocyte differentiation marker intestinal alkaline phosphatase is multifactorial. Surgical Forum 2001;1-2.
44. Archer SY, Tang R, Kim H-J, and Hodin RA. VX-563: A novel butyrate prodrug induces differentiation and the program of cell cycle inhibition in colon cancer cells. Surgical Forum 2001:254-255.
45. Duda RB, Kang SS, Archer SY, Meng S, Hodin RA. American ginseng transcriptionally activates p21 mRNA in breast cancer cell lines. J Kor Med Sci. 2001; 16 S54-S60.
46. Hinnebusch BF, Ma Q, Henderson JW, Siddique A, Archer SY, and Hodin RA. Enterocyte response to ischemia is dependent on differentiation state. J Gastrointest Surg 2002;6:403-409.
47. Hinnebusch, B, Meng S, Wu J, Archer SY, Hodin RA. Short chain fatty acids and colon cancer cell phenotype:The link to histone hyperacetylation. J Nutrition 2002;132:1012-1017.
BF Hinnebusch, JW Henderson, A S, MS Malo, W Zhang, MA Abedrapo, RA Hodin. Transcriptional activation of the enterocyte differentiation marker intestinal alkaline phosphatase is associtaed with changes in the acetylation state of histone H3 at a specific site within its promoter region in vitro. J Gastrointest Surg 2003;7:237-45.
Selected Chapters/Reviews
48. Archer SY, Hodin RA. Histone acetylation and cancer. Current Opinion in Genetics and Development Vol 9, No.2: April 1999. Current Biology Publications, ed. R Lasky and MP Scott.
49. Hodin RA. Maintaining Gut Homeostasis: The Butyrate-NF-kB Connection. Gastroenterology, 2000 118:798-801
50. Archer SA and Hodin RA. The p21 gene. In Encyclopedia of Molecular Medicine, Creighton TE, et. al., editors, New York: John Wiley and Sons, Inc.
51. Archer SY, Hodin RA. Intestinal Regeneration and Adaptation Models. In Surgical Research, Souba WW, and Wilmore DW, editors. San Diego: Academic Press, 2001. 557-571
Pancreatic Research Laboratory
Principal Investigators:
Andrew L. Warshaw, M.D.
Carlos Fernández-del Castillo, M.D.
Sarah P. Thayer, M.D., Ph.D.
Group Members:
Bozena Antoniu, M.S.
Corinne Nielsen, M.S.
Guido Alsfasser, M.D.
Li Li, M.D. The laboratory has been active since 1983, and from 1989 on has had, at any given time, two or three research fellows as well as a research technician or technologist. Its focus has been pancreatic disease, in particular, pathogenesis of acute pancreatitis and pancreatic carcinogenesis. Research fellows typically spend two years in the lab, and in addition to carrying their own research projects, collaborate with research projects of the other fellows in the lab, and occasionally have been involved in clinical studies as well.
Current projects include:
Principal Investigator:
Carlos Fernández-del Castillo, M.D.
The Role of Activated Protein C in Acute Pancreatitis:
This exciting new drug decreased mortality in severe sepsis in a large multicenter trial. Beside its anticoagulant and pro-fibrinolytic effects, experimental data show many different properties, including anti-inflammatory, anti-ischemic and anti-apoptotic properties. Since there are no data on the use of Activated Protein C in pancreatitis, we evaluate its effect on the course of this disease in an experimental model of necrotizing pancreatitis.
The Role of Tumor Necrosis Factor a (TNFa) in Acute Pancreatitis:
A substantial production and release of TNFa during acute pancreatitis (AP) is believed to be a major source of distant organ dysfunction in the course of the disease. In prior studies we have been unable to show an elevation of plasma TNFa during AP. We hypothesize that plasma TNFa is susceptible to degradation by circulating pancreatic proteases. In further experiments we were able to demonstrate degradation and inactivation of TNFa by trypsin, elastase and chymotrypsin; we suggest that its enzymatic degradation limits any substantial role in systemic pathophysiology.
Effects of Troponin 1 on Human Endothelial Cells and Pancreatic Cancer:
Antiangiogenesis agents have been promising in inhibiting cancer implantation and growth. Troponin 1 is an anti-angiogenic compound isolated from bovine cartilage. We studied its effects on a) endothelial cell tube (capillary progenitor) formation, b) endothelial cell division, c) induction of intercellular adhesion molecule-1 (ICAM-1) by pancreatic cancer cells (CAPAN-1) and d) growth of pancreatic cancer liver metastases in the mouse, and were able to show that Troponin I has an anti-angiogenic effect in pancreatic cancer. In-vitro it inhibits pre-vessel tube formation, endothelial cell division, and ICAM-1 upregulation by cancer cells, and in-vivo it reduces metastases from pancreatic cancer to the liver in a mouse model. Further studies will focus on the mechanism of action of Troponin I in the treatment of pancreatic carcinoma.
The Role of Matrix Metalloproteinase in Neutrophil Migration During Lung Injury in Acute Necrotizing Pancreatitis:
Leukocyte-endothelial interaction is a key factor in the pathogenesis of pulmonary injury seen in acute pancreatitis. This interaction is dependent on adhesion molecules that allow for rolling and sticking of neutrophils. The final step in the migration of the neutrophil through the endothelial barrier depends on proteolytic degradation of the basal membrane. This requires upregulation of matrix metalloproteinase, and can be potentially arrested with MMP inhibitors.
Near-Infrared Confocal Microscopy for Evaluation of Pancreatic Disease:
In collaboration with the Wellman Laboratories of Photomedicine, we are exploring the use of near-infrared confocal microscopy both in vivo and ex vivo in normal pancreas, pancreatitis, and pancreatic cancer. This may prove to be a unique tool for the evaluation of microcirculation and angioarchitecture of both inflammatory and malignant pancreatic disease.
Principal Investigator:
Sarah P. Thayer, M.D., Ph.D.
The principal focus of this investigator is to understand the molecular determinants that may be critical and central to the development and biologic behavior of this malignancy.
Sonic Hedgehog (Shh) Links Altered Developmental Programs to Pancreatic Neoplasia:
Our preliminary data reveals that Shh, an important developmental gene, plays a critical and early role in the development of human pancreatic ductal malignancy. Misexpression of Shh in the pancreas results in the formation of tubular complexes that histologically and genetically resembles precursor lesions to invasive cancer. Our future line of investigation is to determine if Shh is sufficient to cause pancreatic cancer.
Conditional Transgenic Mouse Models:
Our first generation Pdx-Shh transgenic mouse, in which Shh expression is controlled by the pancreatic specific promoter Pdx-1, revealed that Shh misexpression resulted in precursor lesions to pancreatic cancer. To better define the role of Shh in the progression of pancreatic cancer, we are presently developing a conditional Shh mouse in which the pancreatic-specific expression of Shh can be turned on and off.
Preclinical Investigation into the Effects of Shh Pathway Agonist and Antagonists on the Biologic Behavior of Pancreatic Cancer:
To determine whether inhibition of this pathway using small molecule antagonists will have any significant impact on the biologic behavior of pancreatic cancer.
Investigation into the Role of NF-kB in Activation of the Sonic Hedgehog Gene:
Shh is activated early in response to inflammation. Inflammatory states have been linked causally to many cancers, including pancreatic cancer. The pro-inflammatory mediator NF-kB appears to upregulate Shh expression. In order to investigate the role of NF-kB we use a recombinant adenoviral vector, which overexpressed IKK-beta a known activator of NF-kB. This system allows us to study the mechanism of Shh activation.
Characterizing c-kit Overexpression in Pancreatic Cancer:
Shh overexpression appears to drive the abnormal expression of c-kit within the neoplastic pancreas. c-kit is a proto-oncogene that encodes a receptor, tryrosine kinase, which has been found to be an important etiologic agent in the transformation of other solid tumors such as GIST. Here we investigate the relationship between Shh expression and c-kit as well as the effect of c-kit over-expression in pancreatic tumor progression.
Preclinical Investigation into the Effects of c-kit Pathway Inhibition with STI-571:
To determine whether inhibition of the c-kit, tyrosine kinase pathway, will have any significant impact on the biologic behavior of pancreatic cancer.
Lineage Analysis of Pancreatic Cancer:
Ductal adenocarcinoma is the most common type of primary malignancy of the pancreas. Despite the ductal phenotype of most human pancreatic carcinomas, there is still considerable debate regarding the cell origin of pancreatic adenocarcinoma, and it remains a critical unanswered question. Recent advances in conditional transgenic technology have provided tools for conclusively determining cell lineage in mice using targeted gene recombination. Genomically tagged mice will be subjected to pancreatic cancer induction. Cell-type-specific tags will finally allow determination of initiator cell type. back to top |
