2011 — 2013 |
Hartz, Anika M.s. |
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. |
Blood-Brain Barrier P-Glycoprotein: a New Target For Alzheimer's Disease @ University of Minnesota
DESCRIPTION (provided by applicant): We have a fundamental lack in understanding the mechanism that reduces P-glycoprotein (P-gp) expression and transport activity at the blood-brain barrier in Alzheimer's disease (AD). Lack of this knowledge is a significant clinical problem since it prevents development of an effective therapy to enhance AB clearance from the brain, lower AB brain levels, and thus prevent cognitive decline in AD. The long-term goal of the investigator is to better understand the molecular mechanisms that regulate blood-brain barrier function in neurodegenerative disorders, a goal which may lead to new therapeutic strategies to treat AD. The objectives of this particular application are to identify the mechanism responsible for P-gp reduction in AD, to validate this mechanism as a target to protect P-gp, and to test a novel therapeutic strategy for restoring P-gp. Accomplishing these objectives is expected to reduce A[unreadable] brain levels and improve cognition in AD. Based on preliminary data, the central hypothesis is that A[unreadable] mediates proteasomal degradation of P-gp, that blocking proteasomal degradation protects P-gp, and that restoring P-gp levels through PXR activation reduces A[unreadable] brain burden and improves cognition in mice with AD. The rationale for the proposed research is that identifying the mechanism that reduces brain capillary P-gp and protecting and/or restoring P-gp to improve A[unreadable] brain clearance will potentially provide novel therapeutic targets to lower A[unreadable] brain levels in AD. To accomplish the objectives of this application, we will test our central hypothesis by pursuing the following three specific aims: 1) Identify the mechanism of A[unreadable]-mediated P-gp reduction at the blood-brain barrier. 2) Validate the ubiquitin-proteasome system as a target to protect P-gp in an AD mouse model. 3) Develop a therapeutic strategy to reduce cognitive decline in an AD mouse model. In Aim 1, we will inhibit the ubiquitin-proteasome system to identify the steps involved in A[unreadable]-mediated P-gp reduction, and determine expression, transport activity, and ubiquitination of P-gp. In Aim 2, we will treat hAPP mice with inhibitors of the ubiquitin-proteasome system, monitor P-gp expression, transport activity, and ubiquitination, and measure A[unreadable] brain levels. We will conduct brain perfusion to assess P-gp activity in vivo and perform tail-flick assays to determine the consequence of changes in P-gp. In Aim 3, we will con- duct a 2-year PCN-feeding study with hAPP mice to assess the long-term therapeutic effect of PXR-mediated P-gp restoration on AB brain levels. P-gp expression and transport activity, A[unreadable] brain load, and cognition will be periodically determined. The proposed research is innovative because it focuses on two independent strategies designed specifically to enhance A[unreadable] clearance from the brain in AD. The proposed research is significant because it holds the promise of two new therapeutic strategies to lower A[unreadable] brain burden and slow progression of AD. The proposed research is translational because drugs for either strategy, inhibition of the ubiquitin- proteasome system and PXR activation, are currently on the market, and both therapeutic strategies could potentially be translated into the clinic for the treatment of AD patients. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will significantly advance understanding of blood-brain barrier function in brain diseases and potentially provide new opportunities for improving treatment of Alzheimer's disease. Worldwide, millions of people are currently affected by Alzheimer's disease and patient numbers will increase tremendously over the next decades. Thus, the proposed research is relevant to the mission of the NIH/NINDS, which is to reduce the burden of neurological disease.
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0.925 |
2014 — 2015 |
Hartz, Anika M.s. |
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. |
Blood-Brain Barrier P-Glycoprotein a New Target For Alzheimers Disease
DESCRIPTION (provided by applicant): We have a fundamental lack in understanding the mechanism that reduces P-glycoprotein (P-gp) expression and transport activity at the blood-brain barrier in Alzheimer's disease (AD). Lack of this knowledge is a significant clinical problem since it prevents development of an effective therapy to enhance AB clearance from the brain, lower AB brain levels, and thus prevent cognitive decline in AD. The long-term goal of the investigator is to better understand the molecular mechanisms that regulate blood-brain barrier function in neurodegenerative disorders, a goal which may lead to new therapeutic strategies to treat AD. The objectives of this particular application are to identify the mechanism responsible for P-gp reduction in AD, to validate this mechanism as a target to protect P-gp, and to test a novel therapeutic strategy for restoring P-gp. Accomplishing these objectives is expected to reduce A¿ brain levels and improve cognition in AD. Based on preliminary data, the central hypothesis is that A¿ mediates proteasomal degradation of P-gp, that blocking proteasomal degradation protects P-gp, and that restoring P-gp levels through PXR activation reduces A¿ brain burden and improves cognition in mice with AD. The rationale for the proposed research is that identifying the mechanism that reduces brain capillary P-gp and protecting and/or restoring P-gp to improve A¿ brain clearance will potentially provide novel therapeutic targets to lower A¿ brain levels in AD. To accomplish the objectives of this application, we will test our central hypothesis by pursuing the following three specific aims: 1) Identify the mechanism of A¿-mediated P-gp reduction at the blood-brain barrier. 2) Validate the ubiquitin-proteasome system as a target to protect P-gp in an AD mouse model. 3) Develop a therapeutic strategy to reduce cognitive decline in an AD mouse model. In Aim 1, we will inhibit the ubiquitin-proteasome system to identify the steps involved in A¿-mediated P-gp reduction, and determine expression, transport activity, and ubiquitination of P-gp. In Aim 2, we will treat hAPP mice with inhibitors of the ubiquitin-proteasome system, monitor P-gp expression, transport activity, and ubiquitination, and measure A¿ brain levels. We will conduct brain perfusion to assess P-gp activity in vivo and perform tail-flick assays to determine the consequence of changes in P-gp. In Aim 3, we will con- duct a 2-year PCN-feeding study with hAPP mice to assess the long-term therapeutic effect of PXR-mediated P-gp restoration on AB brain levels. P-gp expression and transport activity, A¿ brain load, and cognition will be periodically determined. The proposed research is innovative because it focuses on two independent strategies designed specifically to enhance A¿ clearance from the brain in AD. The proposed research is significant because it holds the promise of two new therapeutic strategies to lower A¿ brain burden and slow progression of AD. The proposed research is translational because drugs for either strategy, inhibition of the ubiquitin- proteasome system and PXR activation, are currently on the market, and both therapeutic strategies could potentially be translated into the clinic for the treatment of AD patients.
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0.914 |
2018 |
Hartz, Anika M.s. |
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. |
Restoring Blood-Brain Function to Improve Cognition in Alzheimer's Disease
Increasing evidence indicates that blood-brain barrier dysfunction contributes to cognitive decline in Alzheimer's disease (AD). Two key elements of barrier dysfunction include 1) reduced levels of the blood-brain barrier trans- porter P-glycoprotein (P-gp) that clears A? from the brain, and 2) barrier leakage, both of which have been linked to A? brain accumulation and cognitive impairment. While increasing evidence shows A? involvement in barrier dysfunction, the underlying mechanisms remain to be fully defined. Moreover, therapeutic strategies to restore barrier function are currently not available. Thus, there is an unmet critical need to define the mechanism(s) that lead/s to barrier dysfunction and to develop effective intervention strategies to help restore barrier function in AD. Absent effective strategies, achievement of therapeutic advances in AD will likely remain challenging. The long-term goal of the investigator is to identify molecular pathways involved in regulating blood-brain barrier function that, when disrupted, contribute to brain disease, and that can be exploited for developing new thera- peutic strategies. The overall objective in this application is to establish a novel combination therapy for AD by targeting the underlying causes of barrier dysfunction in a mouse AD model to restore barrier function and slow the rate of cognitive decline. Based on preliminary data the central hypothesis of this project is that restoring blood-brain barrier function will lead to lower brain A? levels and slow the rate of cognitive decline in humanized PXR/APP mice. The rationale for this research is that providing proof-of-concept that restoring barrier function will reduce cognitive decline in experimental animals would establish a framework for future clinical trials in AD patients. This hypothesis will be tested by pursuing three specific aims: 1) Identify the signaling pathway responsible for A?-mediated P-gp reduction at the blood-brain barrier. 2) Determine the underlying mechanism(s) responsible for A?-mediated barrier leakage, and 3) Develop a combination therapy to restore barrier function in a mouse AD model. Under Aim 1, the mechanism of A?-mediated reduction of P-gp protein expression and activity levels will be assessed in isolated healthy human brain capillaries. Under Aim 2, key signaling steps that trigger barrier leakage will be determined in brain capillaries from healthy individuals and from AD patients. Under Aim 3, the therapeutic benefit of a combination therapy involving PXR activation and scavenging reactive oxygen species to restore barrier function, lower A? brain burden, and slow the rate of cognitive decline will be assessed in a humanized PXR/APP mouse model. The proposed research is innovative, because it represents a substan- tive departure from the status quo by shifting the focus to a disease-modifying combination therapy aimed at two new molecular targets to restore barrier function and improve clinical symptoms. The proposed research is significant because it holds the promise of a novel therapeutic approach to restore barrier function that has high translational potential for clinical use to advance treatment of AD patients. Ultimately such knowledge likely will be applicable to other conditions with underlying barrier dysfunction.
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0.914 |