The overall hypothesis of this proposal is that Ubiquilin1 suppresses critical signaling pathways that drive the pathogenesis of both Alzheimer's disease and cancer. These two diseases represent two of the largest burdens on the healthcare systems in all developed countries. In the U.S. the annual national expenditure for these two diseases combined is ~$300 billion dollars. Currently in the U.S. there are ~5.4 million people living with Alzheimer's disease and there will be ~1.7 million new cancer cases diagnosed this year. Only by understanding the basic molecular, biochemical and genetic causes of these diseases will we be able to make significant progress in treating these patients. Interestingly, it has been reported, but largely ignored, that there are common signaling pathways that are altered to drive the onset of both Alzheimer's disease and cancer. This proposal seeks to understand how the of scaffold protein, Ubiquilin1, regulates seemingly opposing cellular outcomes in epithelial cells and neuronal cells. Loss of Ubiquilin1 in epithelial cells increases proliferation and migration, whereas in neuronal cells, it causes cell death. Amazingly, there are a number of additional signaling pathways that behave in a similar cell-type and context-dependent manner, including amyloid precursor protein (APP), growth factor receptors (such as IGF1R) and focal adhesion complexes, such that aberrant activation of processes contributes to both tumorigenic phenotypes, as well as progression of Alzheimer's disease. We are the first to show that loss of Ubiquilin1, as seen in cancer and Alzheimer's disease, causes increased growth factor receptor signaling and increased focal adhesion formation and signaling. In this proposal we will examine the detailed molecular and biochemical regulation of these processes by Ubiquilin1 and we will examine the cell-type and context-dependent differences of Ubiquilin1 function in epithelial and neuronal cells. This information will shed light on the basic mechanisms that contribute to multiple diseases afflicting millions of people every year.

Public Health Relevance

Alzheimer's disease and cancer are seemingly caused by contrasting cellular processes; aberrant cell death for Alzheimer's disease and aberrant cell survival for cancer. The family of adapter proteins, Ubiquilins, are lost in both cancer and in Alzheimer's disease. The goal of this proposal is to determine how Ubiquilin proteins normally function to keep epithelial cells from aberrantly proliferating, while keeping neuronal cells from dying.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA193220-04S1
Application #
9717618
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2015-08-07
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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