Christopher D. Heinen, Ph.D.Associate Professor, Department of Medicine
Investigator, Neag Comprehensive Cancer Center and Center for Molecular Medicine
Director, Graduate Program in Molecular Biology and Biochemistry
|B.S.||Northwestern University||Biomedical Engineering|
|Ph.D.||University of Cincinnati College of Medicine||Molecular Genetics|
|Postdoctoral||Thomas Jefferson University|
|Name of Award/Honor||Awarding Organization|
|Research Scholar Award||American Cancer Society|
|Wendy Will Case Cancer Fund Research Grant Award|
|Albert J. Ryan Fellowship Award, 1996-1998||University of Cincinnati College of Medicine|
|Name & Description||Category||Role||Type||Scope||Start Year||End Year|
|International Society for Gastrointestinal Hereditary Tumors||Research Committee||External||International||2011|
|The American Society for Microbiology||Professional/Scientific Organization||Member||External||National||2009|
|National Institute of General Medical Sciences Minority Biomedical Research Program||Advisory Committee||Ad Hoc Reviewer||External||National||2009|
|American Association for Cancer Research||Professional/Scientific Organization||Member||External||National||2006|
Colon cancer is the third most common malignancy in men and women and ranks behind only lung cancer in cancer deaths. The most common hereditary disease that predisposes patients to colorectal cancer is Lynch syndrome (LS) which stems from mutations in the mismatch repair (MMR) genes. In addition to its role in LS, flawed MMR has been implicated in 15-40% of sporadic colorectal and other extracolonic tumors indicating a more general role for MMR in tumor protection. Although many functional details of the MMR proteins have emerged, the mechanism by which flawed MMR contributes to tumorigenesis is not fully understood. Faulty MMR results in an elevated mutation rate (mutator phenotype), which has been proposed to lead to an accumulation of oncogene and tumor suppressor mutations that ultimately cause cancer. More recent work has revealed that MMR proteins play an important role in cell cycle arrest and apoptosis in response to certain DNA damaging agents. Thus, MMR mutations may affect tumorigenesis through multiple mechanisms. Our laboratory is interested in understanding what functions of the MMR system are affected during tumorigenesis.
We are addressing this broad question through a multi-pronged approach. First, we are examining how the biochemical and biophysical properties of MMR proteins are affected by cancer-associated missense mutations. Missense mutations of at least two MMR genes MSH2 and MSH6 have been linked to LS families providing a tool whereby full-length proteins with single amino acid alterations can be studied to determine how these alterations affect function. The MSH2 and MSH6 proteins form heterodimers in cells that recognize DNA lesions and initiate the repair process. Our laboratory utilizes purified human MSH2-MSH6 heterodimers in a series of in vitro biochemical and biophysical assays to learn about the normal biochemical mechanism as well as the consequences of cancer-associated mutations on this mechanism. Secondly, we are examining the cellular functions of the MMR proteins and the effects of cancer-causing missense mutations by studying how these mutant proteins perform in DNA repair, cell cycle checkpoint signaling, apoptosis signaling and other functional assays. Most recently, we have begun to characterize the function of the MMR pathway in human pluripotent stem cells and are using gene targeting approaches to introduce missense mutations into the endogenous MMR gene loci. Finally, we are interested in identifying proteins that interact with the normal MMR proteins and in determining how these interactions are affected during tumorigenesis.
See Dr. Heinen's NBC Connecticut interview on the importance of colon cancer screening on NBC Connecticut at: http://today.uchc.edu/headlines/2010/mar10/coloncancer.html
Accepting Lab Rotation Students: Fall '17, Spring '18
Lab Rotation Projects
The research in my laboratory involves an array of techniques from biochemistry to cell biology to address the fundamental question of why mutations in DNA mismatch repair genes cause cancer. We are predominantly interested in using cancer-associated missense mutations of the hMSH2 and hMSH6 genes to understand the functions of mismatch repair affected during colorectal tumorigenesis. Projects include:
– Biochemical and biophysical characterizations of the wild-type and mutant MSH2-MSH6 heterodimers.
– Using cell culture models including human pluripotent stem cells to study the functions of mutant MSH2 and MSH6 in damage repair and response.
– Examining the pre-neoplastic colorectal lesions aberrant crypt foci for defects in mismatch repair.
Other projects available and can be discussed depending on student’s interest.
|Title or Abstract||Type||Sponsor/Event||Date/Year||Location|
|The Mechanism of the Mismatch Repair-Dependent DNA Damage Response||Talk||Society of Toxicology 52nd Annual Meeting||2013||San Antonio, TX|
|The Molecular Mechanism of the Mismatch Repair-Dependent DNA Damage Response||Talk||University of Massachusetts Medical School||2013||Worcester, MA|
|Panel for Postdoctoral Fellows: The pathway(s) to your own lab||Panel Discussion||American Society for Biochemistry and Molecular Biology Graduate and Postdo||2013||Boston, MA|
|The Challenge of Mismatch Repair Gene Missense Variants: How Understanding Molecular Mechanism Can Help||Talk||University of Vermont College of Medicine||2013||Burlington, VT|
|Human Disease as a Model for Mismatch Repair Mechanism||Talk||Environmental Mutagen Society 43rd Annual Meeting||2012||Bellevue, Washington|
|The Mismatch Repair Molecular Mechanism and the Missense Variant Mystery||Talk||Massachusetts Institute of Technology||2012||Cambridge, MA|
|Panel for Postdoctoral Fellows: The pathway(s) to your own lab||Panel Discussion||American Society for Biochemistry and Molecular Biology Graduate and Postdo||2011||Washington, D.C.|
|DNA Mismatch Repair Function in Human Disease||Talk||Hospital Clinico San Carlos, Molecular Oncology Branch||2011||Madrid, Spain|
|The Molecular Mechanisms of Mismatch Repair||Talk||American Society for Human Genetics Annual Meeting||2010||Washington, D.C.|
|Reverse Translational Research: What Lynch Syndrome Patients Can Teach Us About Mismatch Repair Mechanism||Talk||Princeton University, Department of Molecular Biology||2010||Princeton, NJ|
|The Functions of DNA Mismatch Repair Affected in Hereditary Colon Cancer||Talk||Yale University, Department of Molecular Biophysics and Biochemistry||2010||New Haven, CT|
|The Functions of DNA Mismatch Repair Affected in Hereditary Colon Cancer||Talk||The State University of New York at Buffalo School of Medicine and Biomedical Sciences||2010||Buffalo, NY|
|Nuclear Reorganization of Mismatch Repair Proteins in Response to DNA Damage||Talk||American Society for Microbiology Conference on DNA Repair and Mutagenesis||2009||Whistler, Canada|
|The Mechanism of DNA Mismatch Repair: Lessons from Hereditary Non-Polyposis Colon Cancer||Talk||Louisiana State University Health Center, Scott Cancer Center||2008||New Orleans, LA|
|Hereditary non-polyposis colon cancer and the role of DNA mismatch repair in cancer||Talk||Wesleyan University, Molecular Biology and Biochemistry Department||2008||Middletown, CT|