Exocrine pancreas disease affects over 250,000 individuals in the U.S. each year, placing significant burden on the healthcare system. The major exocrine pathologies (pancreatitis, pancreatic cancer) initiate from damaged acinar cells that dedifferentiate to a progenitor cell state. In some cases, the damaged cells can regenerate and undergo a redifferentiation/maturation process that establishes organ recovery. Although acinar cell regeneration has been documented, the transcriptional pathways that control regeneration and differentiation responses are poorly understood. To exploit these regulatory pathways for possible therapeutic strategies will require new and innovative approaches that better define acinar cell biology. The long-term goals of this study are to identify the transcripton networks that govern acinar cell function in healthy and in regenerating adult organs. The objective is to determine how acinar and progenitor transcription factors influence acinar cell regeneration and differentiation events. Our central hypothesis is that misregulation of these transcription networks, in response to cell damage, leads to cell dedifferentiation, cell expansion and redifferentiation back to a healthy acinar cell state. This hypothesis will be tested by pursuing two Specific Aims - (1) identify how acinar and progenitor transcription factors control acinar regeneration events during organ injury and (2) establish how the acinar-specific transcription factor MIST1 directs exocrine function in healthy and diseased cells. The goals of these complementary aims will be accomplished using genetically engineered mouse models that permit gain-of-function and loss-of-function strategies to study the regulatory networks involved in acinar cell regeneration and differentiation. The rationale for the proposed research is that these approaches will be the first to examine how specific acinar and progenitor transcription pathways interface to drive tissue repair upon pancreatic injury. This contribution i significant because it will (i) define epigenetic changes in key regulatory genes during injury and recovery, (ii) test if progenitor pathways are essential to producing a proliferative cell populatin, (iii) identify intracellular pathways by which MIST1 induces acinar cell maturation events, and (iv) establish if these pathways are misregulated in patient samples. The proposed research is innovative because it represents a new and substantial departure from the status quo, by approaching acinar cell replacement from both a dedifferentiation and acinar maturation pathway. The discoveries made will greatly advance the current knowledge of the events associated with acinar cell recovery and are expected to drive future efforts in developing new strategies to harness the regenerative capabilities of acinar cells for remodeling the exocrine and endocrine pancreas. These discoveries will have an important positive impact because defining the biological processes involved in acinar cell homeostasis will provide new opportunities for more effective therapeutics against pancreatic disease.

Public Health Relevance

The proposed research is relevant to public health because discovery of the transcription networks that control acinar cell regeneration, differentiation and maturation will identify key pathways that are critical to maintaining a healthy acinar cell and provide a new vision for improved patient therapies. Thus, the proposed research is relevant to NIDDK's mission of fostering creative discoveries and innovative research strategies for digestive disease to improve people's health and quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK055489-15
Application #
8627906
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
2000-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$324,513
Indirect Cost
$107,013
Name
Purdue University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Lee, Hoyoung; Kim, Yeji; Schweickert, Patrick G et al. (2014) A photo-degradable gene delivery system for enhanced nuclear gene transcription. Biomaterials 35:1040-9
Shi, G; DiRenzo, D; Qu, C et al. (2013) Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32:1950-8
Direnzo, Daniel; Hess, David A; Damsz, Barbara et al. (2012) Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. Gastroenterology 143:469-80
Hess, David A; Humphrey, Sean E; Ishibashi, Jeff et al. (2011) Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice. Gastroenterology 141:1463-72
Garside, Victoria C; Kowalik, Agnes S; Johnson, Charis L et al. (2010) MIST1 regulates the pancreatic acinar cell expression of Atp2c2, the gene encoding secretory pathway calcium ATPase 2. Exp Cell Res 316:2859-70
Huh, Won Jae; Esen, Emel; Geahlen, Jessica H et al. (2010) XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum. Gastroenterology 139:2038-49
Nam, Ki Taek; Lee, Hyuk-Joon; Sousa, Josane F et al. (2010) Mature chief cells are cryptic progenitors for metaplasia in the stomach. Gastroenterology 139:2028-2037.e9
Shi, Guanglu; Zhu, Liqin; Sun, Yan et al. (2009) Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136:1368-78
Rovira, Meritxell; Delaspre, Fabien; Massumi, Mohammad et al. (2008) Murine embryonic stem cell-derived pancreatic acinar cells recapitulate features of early pancreatic differentiation. Gastroenterology 135:1301-1310, 1310.e1-5
Nozaki, Koji; Ogawa, Masako; Williams, Janice A et al. (2008) A molecular signature of gastric metaplasia arising in response to acute parietal cell loss. Gastroenterology 134:511-22

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