The IPM supports a variety of projects across Penn State Hershey.
Amyotrophic lateral sclerosis. An ongoing collaboration between Dr. Zachary Simmons, director of the Neuromuscular Program at Penn State Hershey Medical Center, and investigators in the IPM addresses the genetic underpinnings of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. ALS is a progressive, fatal neurodegenerative disease that causes weakness and paralysis, with approximately 10% of the cases being inherited. By determining the genomic sequences of patients from the Penn State Hershey Neurosciences Institute’s ALS clinic, IPM investigators have identified the causative mutation in several patients with inherited ALS and are working to understand the basis for the disease in those with sporadic ALS. These data should allow clinicians to design improved clinical trials in a search for better treatments, to better predict the progression of a patient’s disease, and to identify targets for the development of new drugs.
Autism spectrum disorder. Greater than 1% of children in this country present with some form of ASD. Building on research conducted by Dr. Daniel Notterman on families with monozygotic twins exhibiting discordant ASD diagnoses, IPM investigators have identified a number of candidate genes that may contribute to the onset and progression of ASD. This research represents a close collaboration among investigators in the IPM, the Penn State Genomics Institute at University Park, Children’s Specialized Hospital and the Autism Clinic at Penn State Hershey.
Diverticulitis. Approximately 1-2% of people in this country will require surgery for diverticulitis, a painful intestinal disease that can lead to perforation of the colon. In collaboration with Dr. Walter Koltun, director of the Inflammatory Bowel Disease Institute at Penn State Hershey, IPM investigators are exploring the hypothesis that host genetic factors predispose individuals to the development of diverticulitis, the identification of which can help disease management as well as direct future research into the pathophysiology of the ailment. Examining the genomic sequence of afflicted and non-afflicted members of several families in which several members of the family present with severe, early onset disease, IPM investigators have identified several candidate genes that may contribute to the onset and progression of the disease.
Epilepsy. Working with Dr. Frank Gilliam in the Department of Neurology, investigators in the IPM are exploring the causes and treatment of epilepsy. Dr. Gilliam applies state of the art electrophysiology imaging techniques to identify the hyperactive region of the brain of patients suffering from severe epilepsy and uses that information to guide neurosurgeons to excise the epileptogenic regions. IPM investigators are analyzing the excised tissue to determine the genetic, epigenetic or metabolic differences between the affected region and the normal region of the brain that could account for the hyperactivity of the abnormal region. In addition, investigators are beginning to explore the genetics of patients who exhibit severe adverse events to otherwise effective drugs designed to control seizures, in hopes of being able to make these drugs more widely useable.
Intracranial Aneurysms. Aneurysms, or balloon-like dilatations of the arterial wall, can occur in arteries within the brain, particularly downstream of branch points. These aneurysms are sensitive to rupture, which could result in intracranial hemorrhage, stroke or death. Accordingly, being able to identify patients susceptible to aneurysms would allow monitoring and, when identified, prophylactic treatment of the aneurysm. Dr. Robert Harbaugh, chair of the Department of Neurosurgery at Penn State Hershey, has identified families in which susceptibility to occurrence of aneurysms appears to be inherited. IPM investigators are exploring the genomic sequences of members of these families in an attempt to pinpoint the genetic lesion responsible for this susceptibility and thereby provide a prognostic indicator of the likelihood of developing aneurisms.
Parkinson’s Disease. 50,000 Americans present with Parkinson’s Disease each year, which results from selective loss of dopaminergic cells in the Substantia Nigra with associated motor neuron dysfunction, leading to resting tremors, bradykinesia, gait difficulties and rigidity. Working with Dr. Xuemei Huang in the Penn State Hershey Neurosciences Institute, investigators in the IPM are exploring genetic predispositions to Parkinson’s Disease. In particular, Dr. Huang has identified several pairs of monozygotic twins who are discordant in disease presentation, with one individual severely afflicted and the other unaffected. Examining the genomic sequence of these individuals may pinpoint specific genetic lesions that would provide not only a prognostic biomarker but also a potential route to novel treatment.
Osteoporosis and vitamin D deficiency. Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures, predominantly of the hip, spine and wrist. Osteoporosis often arises as a result of vitamin D deficiency, which can generally be treated by vitamin D supplementation. Dr. Edward Fox in the Penn State Hershey Bone and Joint Institute has observed that, while most patients treated with vitamin D supplements show an increased level of circulating vitamin D, some do not. Investigators in the IPM will explore the genetic underpinnings of this lack of response both to understand the mechanism of vitamin D absorption as well as to provide a marker to redirect non-responsive patients to alternative treatments.
Inherited Cancer Syndromes. Approximately 5-10% of all cancers are due to inherited mutations in several known genes. Individuals who inherit one of these mutations will have a higher risk of developing cancer over their lifetime. These syndromes include hereditary breast and ovarian cancer syndrome caused by mutations primarily in the BRCA1 and BRCA2 genes, hereditary non-polyposis colorectal cancer syndrome (HNPCC) or Lynch Syndrome which is characterized by early age onset colorectal and endometrial cancer caused by mutations in the MLH1, MSH2, MSH6 or PMS2 genes, familial adenomatous polyposis or Gardner’s Syndrome a colon cancer predisposition syndrome due to mutations in the APC gene, and multiple endocrine neoplasia (MEN) syndromes in which there is an increased risk to develop tumors of the pituitary, thyroid, parathyroids, adrenals, and pancreas due to mutations in the MENIN and RET genes. Despite the identification of the genes responsible for these syndromes, there are still a number of families in which these cancer are diagnosed who do not have mutations in these genes, and there are families who inherit risk for other types of cancers for which causative genes have yet to be identified. A goal of this project is to identify new genes for inherited cancer syndromes.
Thyroid cancer. IPM investigators are initiating a project with Drs. David Goldenberg and Brian Saunders in the Department of Surgery to study thyroid cancer, a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. While most patients with well-differentiated thyroid cancer present with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. There remains a lack of alternative treatment for patients with these poorly differentiated tumors and these patients have a poor response to conventional treatment. Unfortunately, few cell lines from thyroid tumors that can be grown and studied in the lab are available. One of the objectives of this study is to develop a thyroid cancer cell culture model so that the biological behavior of the cancers can be more effectively analyzed. In addition, this study may better define key genetic and epigenetic changes in thyroid cancer samples from patients that correlate with different clinical outcomes. The information from these studies may lead to better treatment options.
Schizophrenia/bipolar disorder. Working with Drs. Ed Bixler and Erika Saunders within the Penn State Department of Psychiatry and the Pennsylvania Psychiatric Institute, investigators in the IPM are beginning to explore the genetic contributions to schizophrenia and bipolar disorder. By coupling genomic analysis conducted in the IPM with detailed phenotypic stratification of patients through tools recently developed by clinicians in the Department of Psychiatry, we expect to be able to reveal diagnostic biomarkers that will allow clinicians to classify psychiatric disorders with much greater prognostic clarity.
Fracture non-union. Drs. Henry Donahue and Spence Reid in the department of Orthopaedics and Rehabilitation have explored the genetics underlying the failure of patients suffering bone fractures to reknit the bone in a timely fashion. Using a population-based, case controlled study, they have identified several candidate genes in which variant allele in the population may contribute to the delayed fracture healing. Investigators in the IPM plan to extend this study to confirm these assignments and pinpoint the causative genetic variants.
Lung nodules and incipient lung adenocarcinomas. Lung cancer is the leading cause of cancer mortality in the US in both men and women, with an overall survival rate of 15%. One reason for this high mortality is the lack of early detection at a time at which the incipient cancer could be effectively treated. The Penn State Hershey Center for NMR Research has developed a non-invasive method for imaging nodules in the lung of patient that might correspond to early onset lung cancer sites. Investigators in the IPM plan to conduct genomic analysis of biopsies of these lung nodules to determine whether they exhibit genetic hallmarks of early stage cancer. These studies should help validate this new screening procedure and perhaps reduce the mortality of lung cancer.
Age-Related Macular Degeneration. Macular degeneration is an eye disorder that slowly destroys sharp, central vision. Since this generally occurs in individuals over 60, it is often referred to as Age-Related Macular Degeneration of AMD. Wet AMD occurs in only about 10% of people with macular degeneration and results from growth of new abnormal and very fragile blood vessels under the macula. This form of AMD can often be treated with new drugs that block blood vessel formation, such as Avastin or Lucentis. Investigators in the Penn State Hershey Department of Ophthalmology have observed that some patients with Wet AMD fail to respond to Lucentis while others respond quite well. Investigators in the IPM plan to work with clinicians in the Ophthalmology Department to assess whether the differences in response to treatment can be attributed to genetic differences among patients. Identification of such biomarkers should help clinicians provide the most effective treatment.