David A. Hinkle, MD, PhD - US grants
Affiliations: | University of Pittsburgh, Pittsburgh, PA, United States |
Area:
astrocyte-mediated neuroprotectionWebsite:
http://www.pind.pitt.edu/old/PIND_Personnel/Hinkle.htmlWe are testing a new system for linking grants to scientists.
The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
You can help! If you notice any innacuracies, please sign in and mark grants as correct or incorrect matches.
High-probability grants
According to our matching algorithm, David A. Hinkle is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
|---|---|---|---|---|
| 2001 — 2003 | Hinkle, David A | 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. |
Dendrite Involvement in Dopaminergic Neuron Cell Death @ University of Pennsylvania DESCRIPTION (provided by applicant): The goal of this proposal is to begin to identify tile role of the dendrite in l-methyl-4-phenylpyridine (MPP+)-mediated toxicity in dopaminergic neurons as a model of neurodegeneration in Parkinson?s disease (PD). The overall hypothesis is that MPP+ disrupts dendrite function early in the cell death pathway, and that neurotrophic factors such as BDNF, NT-4/5, and/or GDNF may prevent these early dendritic changes, and thus, cell death. The expression and intracellular trafficking of specific candidate and novel mRNAs will be evaluated using expression profiling. Samples will be collected from isolated neurites and cell bodies of individual dopaminergic neurons under various experimental conditions of toxin exposure and growth factor treatment at times which correspond to early degeneration. Active genes will then be further analyzed for changes in abundance and subcellular distribution of their specific proteins by a novel proteomics methodology which was recently developed in this lab. These studies will begin to explore the molecular mechanisms of dendrite involvement in neurodegeneration and neuroprotection using cutting-edge technologies in a system that is highly applicable to PD. |
0.669 |
| 2007 — 2011 | Hinkle, David A | K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
The Potential Role of Dj-1 in Astrocyte-Mediated Neuroprotection @ University of Pittsburgh At Pittsburgh DESCRIPTION (provided by applicant): Oxidative injury is a biochemical hallmark of Parkinson's disease (PD). Genetic studies have shown that deletional mutations in the DJ-1 gene, which encodes a protein that responds to and may protect against oxidative stress, cause familial PD. In sporadic PD, DJ-1 is robustly-expressed within reactive astrocytes in a regional pattern that may be inversely proportional to the degree of pathology. This suggests that DJ-1 may aid in astrocyte-mediated anti-oxidative neuroprotection, and that less PD-vulnerable brain regions may be made so by a greater ability of their resident astrocytes to produce DJ-1. Thus, since astrocytes serve many neuron-supportive functions in the brain, and themselves abundantly survive in PD, these cells may be ideal targets for future disease-modifying therapies that augment specific components of their neuroprotective arsenal. The overall hypotheses of this proposal are that DJ-1 expressing astrocytes are most abundant in low PD vulnerability brain regions, that astrocytes from low vulnerability regions express the most DJ-1 and are the most neuroprotective, and that astrocyte-derived DJ-1 itself is critical to the mechanisms of astrocyte-mediated neuroprotection. The first Aim, then, is to immunohistochemically define the anatomical distribution and abundance of reactive astrocytes throughout the PD brain, characterize their expression of DJ-1 and other selected anti-oxidant molecules, and to correlate these findings with the extent of neurodegeneration within specific brain regions. The second Aim is to evaluate PD-relevant neurotoxins for their ability to stimulate DJ-1 expression in enriched mouse astrocyte cultures prepared from multiple brain regions which, in humans, are known to exhibit variable levels of vulnerability to PD. In this aim, DJ-1 protein and mRNA levels will be quantitated using Western blot/ELISA and ribonuclease protection assay methods, respectively. The third Aim is to evaluate the roles of astrocyte presence, brain region specificity, and astrocytic DJ-1 on astrocyte-mediated neuroprotection against PD-relevant neurotoxins in neuron-astrocyte co-cultures. This Aim will be approached using combinations of wild-type, DJ-1 knock-down/knock-out, and DJ-1 over-expressing astrocytes cultured with wild-type neurons. This proposal is relevant to public health because it endeavors to explore a novel, feasible, and potentially powerful new approach to disease-modifying therapy in Parkinson's disease, a very common and disabling neurological disorder. |
1 |
| 2011 — 2012 | Hinkle, David A | 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. |
Dj-1 in Astrocyte-Mediated Neuroprotection Against Complex I Inhibitors @ University of Pittsburgh At Pittsburgh DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by progressive neuronal loss in multiple brain regions. Particularly affected is the substantia nigra pars compacta (SNpc) of the midbrain. In PD, this region shows degeneration of dopaminergic neurons and deficient mitochondrial respiratory chain complex I activity. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a complex I inhibitor, has caused human parkinsonism by selectively killing SNpc dopaminergic neurons. Several pesticides, including rotenone, also selectively inhibit complex I and cause SNpc dopaminergic neurodegeneration in animal models. Human epidemiological studies have now linked pesticide exposure to an increased risk for PD. One recent study implicated occupational exposure to rotenone. It is therefore plausible that environmental toxicant (pesticide) exposure causes the complex I deficiency seen in PD, and that this mechanism is central to disease initiation and/or progression. Our research goal is to identify natural protective strategies employed by the brain against neurodegeneration induced by complex I-inhibiting environmental toxicants. Ultimately, we hope to exploit these mechanisms to develop novel disease-modifying therapies against PD. Our recent work has identified DJ-1 over-expression in astrocytes as a neuroprotective mechanism against complex I-inhibiting pesticides in vitro. This process appears to involve astrocyte-released factors, and may be particularly relevant to PD because (i) reactive astrocytes over-express DJ-1 in sporadic PD and (ii) mutations that eliminate DJ-1 expression cause familial PD. Thus, we hypothesize that astrocytic DJ-1 over-expression in the human brain may represent a natural neuroprotective attempt against PD. If true, this process may be targetable for augmentation as disease-modifying therapy. To model this possibility in the intact brain, we will assess the capacity of astrocytic DJ-1 over-expression to reduce MPTP-induced SNpc dopaminergic neurodegeneration in transgenic mice (Aim 1). This will be studied using behavioral, immunohistochemical, and biochemical analyses in novel mice, recently developed in our lab, that over- express DJ-1 selectively in astrocytes under control of the glial fibrillary acidic protein promoter. We will also assess the capacity of lentivirus-mediated astrocytic DJ-1 over-expression to perform similarly against rotenone in rats (Aim 2). In each case, we hypothesize that astrocytic DJ-1 over-expression will augment astrocyte-mediated neuroprotection against complex I inhibition. Aim 2 will also test an experimental translational gene therapy approach against pesticide-induced neurodegeneration. In our final Aim we will use analytical chemistry methods to identify the DJ-1-modulated, astrocyte-released soluble factor(s) that carry the neuroprotective activity in our cell culture model. These factors, or the mechanisms they employ, may also generate novel therapeutic strategies against pesticide-induced neurodegeneration and PD. |
1 |