Ph.D. 2000, University of Rochester, Rochester, NY
Phone: 202.687.8928
Fax: 202.687.0617
E-mail: trm36@georgetown.edu
Dr. Mhyre's reasearch focuses on the identification, validation, and further study of peripheral biomarkers in age-related neurodegenerative diseases, specifically late-onset Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, my lab is focused on understanding relationships between the peripheral immune system and the central nervous system and in utilizing these relationships to better understand disease diagnosis, prognosis, and therapies.
AD, the most common age-related neurodegenerative disorder, is a progressive disease that results in the death of specific neuronal populations and a devastating loss of cognitive function. PD is the second most prevalent neurodegenerative disease, which selectively affects the nigrostriatal dopaminergic neuron population and results in specific motoric dysfunction and often other neurological deficits. Together, these diseases affect approximately six million Americans and are estimated to cost the United States economy over $100 billion annually. Unfortunately, current therapies and treatments are only symptomatic and these diseases remain relentlessly progressive. Thus, our need to fully understand the pathogenesis of these diseases and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and to our health care systems.
The etiologies of both AD and PD are currently unknown and diagnosis often occurs only after significant neuron loss and pathology have occurred. However, a variety of postmortem evidence suggests that the pathological hallmarks of AD and PD, and by inference the diseases themselves, begin to occur early in an individual’s life. As such, we hypothesize that disease specific genetic and environmental stressors begin to affect cellular pathways much earlier than even the earliest onset of clinical pathophysiology, which ultimately results in the specific cellular pathologies of these diseases. These stressors, combined with cell-intrinsic compensatory mechanisms, lead to specific, step-wise programs of cellular pathology, progressing to cellular dysfunction, cell death, and ultimate development of the AD or PD phenotype. We propose that these programs are not restricted to the central nervous system (CNS), but represent a systemic pathophysiologic process. One biological system that may be affected and have great clinical utility is the hematopoietic compartment. Like the CNS, the hematopoietic compartment contains long-lived cells that are likely to be affected by systemic pathologic processes that would be reflected in the circulating pool of nucleated cells (e.g. leukocytes). While not fully elaborated, the literature supports the contention that both the CNS and hematopoietic compartments are affected similarly by AD- and PD-dependent processes. We hypothesize that the pathogenesis of these diseases involve systemic processes and that these processes will be reflected in multiple biological compartments and cell types, including neurons and leukocytes. Furthermore, disease specific groups of signature molecules will reflect these pathogenic pathways and will serve as important biomarkers for AD and PD.
Current research is focused upon using biomolecular techniques to identify and validate potential peripheral leukocyte biomarkers in neurodegenerative diseases. We have assembled an initial cohort of subjects grouped into a quad set format. Each quad is composed of age- and gender-matched individuals that are either non-demented control, AD, non-demented PD, or mild cognitive impairment (MCI, perhaps an early form of AD) subjects. This population will form the basis of our discovery project to identify potential peripheral leukocyte biomarkers in neurodegenerative diseases. We have also collected separate cohorts of control and PD subjects and control and AD subjects that we will use to validate disease specific biomolecular profiles. Using this format, we anticipate identifying a range of biomarker profiles, including those that are: 1) general to neurodegenerative disorders (shared among AD, MCI, and PD); 2) representative of early stages of neurodegeneration and dementia (MCI); 3) specific to AD; and 4) specific to PD. In one set of studies we are utilizing exploratory proteomic techniques, including two-dimensional electrophoresis analysis, to identify differentially expressed leukocyte proteins in these subjects. We will then use directed proteomic techniques (Western blots, ELISAs, enzyme activity assays) to validate these profiles in both the original and in subsequent cohorts. A second set of discovery studies is ongoing to analyze differences in RNA transcript profiles using high density microarrays, followed by validation using quantitative real-time PCR and low density microarrays. Finally, we are attempting to expand these studies by increasing our cohort numbers, assessing higher throughput biomolecular technologies, and adding additional subject data, including neuroimaging and improved neuropsychological testing.
The main goal of these studies is to identify and validate, using both exploratory and directed biomolecular methods, peripheral leukocyte molecules that will serve as biomarkers for neurodegenerative diseases. However, these data will not only serve this goal, but are also part of a larger effort, both in human subjects and in animal models of these diseases, with important long-term goals. Using the approaches and data outlined in this proposal, we intend to identify sets of biomarkers that will ultimately: 1) Allow for earlier, presymptomatic diagnosis of AD and PD; 2) Allow for segregation of each of these diseases into molecularly defined and mechanistically dissimilar entities; 3) Establish the biochemical basis for shared peripheral and central neuronal molecular signatures within AD and PD; 4) Identify biochemical pathways important to the pathogenesis, progression, and therapy of these diseases; 5) Relate signature biomarkers with their encoded genes and polymorphisms associated with their regulation, and; 6) Use these methodologies and technologies to identify peripheral biomarkers in similar experiments for other neurodegenerative disorders. We believe that the above and future studies will provide important foundations in our further understanding of neurodegenerative disease pathogenesis, diagnosis, treatment, and potential therapies.
|
