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High-probability grants
According to our matching algorithm, Laurie H. Sanders is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2010 — 2011 |
Sanders, Laurie H |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Dna Damage and Repair in Parkinsons Disease @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): Neurons may be particularly prone to DNA damage by reactive oxygen species due to their high metabolic activity and low levels of antioxidant defenses [1]. Repair of oxidative DNA damage is therefore essential for normal brain function. Very little is known about neuronal DNA repair and therefore it is an important field for investigation. An etiological link to DNA damage via oxidative stress has been implicated in the pathogenesis of Parkinson's disease (PD) [2, 3]. PD is a progressive neurodegenerative disorder that is pathologically characterized largely by the loss of dopaminergic neurons of the substantia nigra. The initial underlying mechanism(s) that triggers neurodegeneration in PD is unknown. Elevated levels of DNA damage were detected in the dopaminergic neurons of the substantia nigra in PD patients [4-6]. It is unclear whether DNA damage is responsible for neuronal loss or is an epiphenomenon of the disease in the surviving neurons. Expression of "GO" enzymes (OGG1, MUTY, and MTH1), proteins involved in the repair of oxidative DNA damage, were also found to be increased in the dopaminergic neurons in the substantia nigra of PD patients [7- 9]. However, the extent to which the GO system acts to prevent DNA damage and/or mutations in both the nuclear and mitochondrial genomes in neurons is presently unclear. The proposed experiments will test the hypothesis that DNA damage is an early event in dopaminergic cell loss in the substantia nigra and that the GO pathway is important in protecting against such oxidative DNA damage. If DNA damage is potentially an underlying mechanism of neuronal degeneration, and GO repair is important in preventing this damage, these represent novel targets for the development of treatments to slow the progression of PD. A combination of molecular, biochemical and cellular techniques using rotenone models of PD and human postmortem brain tissues will be utilized. This proposal has the following two specific aims: (1) Determine the temporal and spatial role of DNA damage in the progressive loss of dopaminergic neurons;and (2) Determine the role of the GO members (OGG1, MutY, Mth1) in the repair of rotenone-induced DNA damage in both in vitro and in vivo models of PD. PUBLIC HEALTH RELEVANCE: Despite significant advances in the PD field over the last couple of decades, there are still major gaps in our understanding of the underlying mechanism(s) contributing to the progressive neurodegenerative process, and a consequent lack of effective therapeutics available to PD patients. Demonstration that nigral dopamine neuron degeneration is related to their propensity to accumulate unrepaired DNA damage could form the basis of novel therapies for neuroprotection in PD and other age-related neurodegenerative disorders. A strategy to slow the progression of PD would have a considerable positive influence on the quality of life for PD patients.
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0.97 |
2021 |
Sanders, Laurie H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Mitochondrial Genome Integrity in Familial and Idiopathic Parkinson's Disease
Abstract Parkinson?s disease (PD) is the most common neurodegenerative movement disorder and over ten million people worldwide are living with PD. To date, treatments are only symptomatic; they do not alter the inexorable progression of the disease. The most common cause of familial and idiopathic PD are mutations in leucine-rich repeat kinase 2 (LRRK2). LRRK2-associated and idiopathic PD demonstrate mitochondrial impairment, however our understanding of the molecular underpinnings of mitochondrial dysfunction in PD is limited. In our efforts to understand the underlying mechanisms driving mitochondrial dysfunction, we found that mitochondrial DNA damage is a shared phenotype amongst both LRRK2-associated and idiopathic PD. Unrepaired mitochondrial DNA damage can have major adverse cellular effects, impacting genetic and protein instability, compromising bioenergetic function, increasing reactive oxygen species, and triggering cell death. Recent preliminary studies by the Sanders lab has found that blocking kinase activity of ATM (a kinase that functions to sense, signal and promote repair of DNA damage) rescues PD-induced mitochondrial DNA damage. We further observed that ATM is activated and initiates the DNA damage response pathway. Interestingly, mitochondrial DNA repair capacity is impaired with a concomitant increase in specific mitochondrial oxidative DNA lesions. The overarching goal of the parental grant to understand how dysfunctional LRRK2 triggers the ATM-mediated DNA damage response pathway, which impairs mitochondrial DNA repair capacity, leading to an increase in mitochondrial DNA damage, ultimately promoting downstream pathogenic PD cascades. Specific to this research supplement, we have discovered that the role of mutant LRRK2 extends to nuclear DNA damage. Based on this data, Dr. Gonzalez-Hunt will determine the molecular identity of the nuclear DNA lesions that are in common between LRRK2 and idiopathic PD. She will learn new technical expertise and methodology, publish impactful research and obtain the key preliminary data for competitive K grants to launch an independent scientific career. Overall this project will directly complement the parental grant and ongoing experiments in the lab to understand shared pathways driven by LRRK2 dysfunction, in order to provide new insights into PD pathophysiology and consequently lead to new therapies.
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