The application outlines 5 years of mentored research with a formal career development plan under the guidance of Dr. Mukesh Jain, a recognized leader in transcriptional and vascular biology. The applicant, Dr. Lalitha Nayak, a clinical scientist with special interest in hemostasis and thrombosis will also be mentored by an Advisory Committee composed of highly successful, NIH-funded physician scientists at Case Western Reserve University (CWRU) with expertise in her area of research. Although Kruppel-like zinc finger transcription factors play an important role in vascular and hematopoietic cell biology, the role of Kruppel-like factor 2 (KLF2) in regulating thrombotic process in vivo is not defined. Nascent observations by the applicant suggest a critical role for myeloid KLF2 in vascular thrombosis. Utilizing a combination of murine models and molecular/cellular approaches, Dr. Nayak will study the role of myeloid transcription factor Kruppel-like factor 2 (KLF2) in the molecular mechanisms and cellular interactions involved in the dynamic process of thrombosis, a major cause for morbidity and mortality worldwide. Further, Dr. Nayak will extend the studies to examine the antithrombotic effects noted with the widely used anti-myeloma agent, proteasome inhibitor Bortezomib.
The specific aims of the proposal include: 1. To investigate the effect of altering myeloid KLF2 on thrombosis: We will use myeloid-specific KLF2 knockout and overexpression mouse lines to conduct vascular thrombosis and examine intercellular interactions during the thrombotic process. 2. To elucidate the molecular mechanisms involved in KLF2's ability to regulate thrombosis: We will employ molecular approaches to elucidate the mechanistic basis of KLF2's ability to alter myeloid pro-thrombotic activity 3. To determine the importance of KLF2 for the antithrombotic effects noted with Bortezomib: We will examine the antithrombotic effect of Bortezomib in myeloid-KLF2 knockout mice to determine the dependency of Bortezomib on KLF2 to produce its antithrombotic effect. This plan is ideally carried out in the Cardiovascular Research Institute (CVRI) at Case Western Reserve University with its distinguished record for training physician-scientists in a rich and collaborative environment. The mentored K08 award will directly advance her scientific development by protecting her effort toward her research project and career development plan. In addition, the career development goal of this project is to help Dr. Nayak transition into an independent investigator with her own laboratory and R01 funding.

Public Health Relevance

Vascular thrombosis is the leading cause for morbidity and mortality worldwide. While it is increasingly appreciated that myeloid cells play a critical role i the initiation and progression of the thrombotic process, the molecular mechanisms governing the complex intercellular interactions that exist between the hematopoietic elements, including platelets and the vasculature remain incompletely defined. Our preliminary data strongly supports a critical role for transcription factor Kruppel-like factor 2 (KLF2) in thrombosis. This grant aims to gain a more precise understanding of the role of myeloid KLF2 in altering thrombosis with the goal to translate these findings towards the development of novel antithrombotic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL121131-01
Application #
8616228
Study Section
Special Emphasis Panel (ZHL1-CSR-X (O1))
Program Officer
Sarkar, Rita
Project Start
2014-09-02
Project End
2019-07-31
Budget Start
2014-09-02
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$130,073
Indirect Cost
$9,635
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106