Vega Lab
Lab Personnel
- Irving E. Vega, PhD, Primary Investigator
- Andrew Umstead
- Jared Lamp
- Ahlam Soliman
- Fabiola Sotomayor-Reinat
Overview
Pathological Tau Aggregation Project
Tau aggregation is a pathological hallmark in Alzheimer’s disease (AD) and other neurodegenerative diseases, known collectively as tauopathies. The lack of effective treatments that prevent or halt tau aggregation contributes to an increasing healthcare and economic burden for patients and caregivers. The evidence so far indicates that, longitudinally, tau undergoes conformation changes that lead to the formation of oligomers and, subsequently, filaments that tend to aggregate further into an ultrastructure known as neurofibrillary tangles (NFTs). An important conundrum related to the pathophysiology associated with tau-mediated neurodegeneration is deciphering the molecular processes that influence the transition of physiological tau monomers to pathological tau toxic species.
Our lab identified EFhd2 as a tau-associated protein that copurified and colocalized with tau filamentous structures found in AD cases. We have primarily focused on studying how the interaction between EFhd2 and tau induces the formation of tau aggregates. Our lab uses a comprehensive approach to study the effect that EFhd2 exert on tau protein dynamics ranging from molecular biology, protein biochemistry, mouse models and human tissue samples.
The overall goal of this project is to assess the role of EFhd2 in tau-mediated neurodegeneration and facilitate the establishment of models that can be used to test potential therapeutics against specific pathological tau toxic species.
Brain Microbial Proteome in Alzheimer’s
Alzheimer’s disease (AD) continues to be a major health issue in the US. Thus, it is imperative to better understand molecular processes that influence brain function and health. Several studies suggest that dysbiosis may modulate the inflammation associated with AD pathobiology. However, the relationship between dysbiosis and disease state is still poorly understood. Currently, there is no evidence of the establishment of a brain microbiota that directly influence the central nervous system, explaining how dysbiosis could lead to neurodegeneration.
Our lab focusses on uncovering the presence of specific bacterial species in normal aging and AD brain, and to enhance the understanding between dysbiosis and neurodegeneration. To achieve these goals, we developed an unbiased proteomics approach and stringent datamining pipeline to identify bacterial proteins in normal aging and AD brain tissue from two different brain banks.
The main goal of this project is to demonstrate that changes in brain microbiota influence health and disease. This information will contribute to understanding the mechanisms underlying the role of dysbiosis in neurodegeneration and will set the basis for a study of restoration and prevention.
Proteome Underlying Selective Vulnerability in Alzheimer’s Project
Studies directed to uncover the molecular environment that foster the generation and accumulation of pathological tau proteins are imperative to cease the epidemic of Alzheimer’s disease (AD) and related dementias. Selective brain vulnerability is a pathological aspect that needs to be better understood. Although aggregation of Ab peptides seems to precede tau pathology, it is the pathological aggregation of aberrantly phosphorylated tau proteins at specific brain regions what directly correlate with clinical presentation.
Our lab focuses on the identification of global proteome changes and differential tau interactome in specific brain regions to uncover factors associated with selective brain vulnerability. We use an integrated proteomics-computational approach to 1) identify tau-associated proteins and differential protein abundance within specific brain regions and 2) systematically characterize their convergence on to a genome-scale protein interaction network that explains selective vulnerability in AD.
The identification of brain region specific tau-induced proteome changes will serve as foundation to better understand molecular mechanisms associated with disease progression and selective vulnerability, which could lead to the development of therapeutic and/or prevention strategies.
Blood 3R/4R tau ratio in Tauopathies Project
Differences in tau’s 3R and 4R isoforms ratio modulate its biological activities and pathobiology. At present, there are no non-invasive diagnostic tools for pre-mortem diagnostic differentiation of tauopathies. Most attention has been placed on detecting pathological tau in CSF of Alzheimer’s disease (AD) versus cognitive normal individuals. But tau biomarkers in blood for AD and other tauopathies is understudied. While aggregation of 3R and 4R is a pathological hallmark of AD, the predominant aggregation of 3R or 4R tau differentiated other tauopathies.
Our lab focuses on 1) determine differences in the detection of tau isoforms in blood constituents in tauopathies; 2) detect differences in tau 3R/4R ratio in blood from different tauopathies; 3) determine the effect that ethnicity has on tau abundance in blood. We developed a targeted mass spectrometry approach to increase detection sensitivity and specificity of 3R and 4R tau isoforms in blood.
Our long-term goal is to establish a simple non-invasive method for differentiating tauopathies.
Blood Biomarkers Variance in Alzheimer’s Disease Project
Alzheimer’s disease (AD) affects more than 5.5 million people in the US, and this number is expected to triple by 2025. Thus, it is imperative to develop better diagnostic tools in order to test potential disease-modifying treatments that could halt this epidemic. AD biomarker strategies using less invasive plasma-based approaches and targeting novel markers may prove to be a way forward for developing a reliable AD diagnostic.
Our lab focuses on the establishment of simple and minimally invasive methods to detect AD associated biomarkers (i.e. tau and Ab peptides), discover novel biomarkers and assess the effect that ethnicity may have on the abundance of these biomarkers in blood. We use quantitative and targeted proteomics approaches.
The successful completion of this project will advance the understanding of AD biomarkers in blood as a diagnostic tool.
Latino Community Network Approach to Address Health Disparities
The prevalence of Alzheimer’s disease (AD) among Latinos is higher than other ethnic groups. Socioeconomic factors contribute to differential access to healthcare, which may increase the risk of developing chronic diseases such as AD. Most studies aimed at understanding the basis of health and healthcare disparities take a unilateral approach where the main goal is the transformation and cultural understanding of the underserved or underrepresented community with the purpose of increasing their participation in research projects. However, the results of these projects and/or expected benefits are not well communicated back to the community, leading to lost opportunities to increase awareness and share information that might have a dramatic impact in reducing healthcare disparities. Hence, current strategies tend to establish a hierarchical status between participants, their healthcare provider and/or the research institutions engaging them, where the authority is perceived to reside with the latter.
Therefore, our lab goal is to close the gap between researchers and underrepresented ethnic groups by utilizing a community network approach that results in increased inclusiveness and knowledge-based empowerment of underrepresented and underserved communities. To achieve this goal, we engaged leaders of the Latino community and healthcare/research institutions in the Grand Rapids area to identify factors that contribute to healthcare disparities and developing transformative action plans that lead to increase access to and equity in healthcare.
The ultimate goal is to develop an inclusive and safe environment that leads to collaboration and contribution of the Latino community in the generation of scientific knowledge and healthcare equity.